N,N-substituted cyclic amine derivatives

ABSTRACT

The invention provides an N,N-substituted cyclic amine compound represented by the following formula (VIII):                    
     wherein A represents an aryl group etc.; E represents a group represented by the formula —CO— or a group represented by the formula —CHOH—; G represents an oxygen atom etc.; J represents an aryl group which may be substituted; R 1  represents a lower alkyl group etc.; Alk represents a linear or branched lower alkylene group; n, v, w, x and y are independent of each other and each represents 0 or 1; and p represents 2 or 3, or a pharmacologically acceptable salt thereof. The compound of the present invention or a salt thereof is effective to treat a disease against which calcium antagonism is effective. The disease may include acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral nerve cell death, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, cerebral circulatory metabolism disturbance, cerebral function disturbance, pain, spasm, schizophrenia, migraine, epilepsy, maniac-depressive psychosis, nerve degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder (generalized anxiety disorder) and diabetic neuropathy.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP99/03900 which has an Internationalfiling date of Jul. 21, 1999, which designated the United States ofAmerica.

INDUSTRIAL FIELD OF THE APPLICATION

The present invention relates to novel N,N-substituted cyclic aminecompounds useful as a calcium antagonist, particularly as anerve-selective calcium antagonist, specifically as an agent fortreating and improving the diseases against which an inhibitory actionon P/Q type calcium channels or an inhibitory action on N type calciumchannels is effective, more specifically as an agent for inhibiting thedeath of nerve cells or for protecting cerebral nerve cells, and furtherspecifically as an agent for treating and improving nerve diseases, andmost specifically as an agent for preventing, treating or improvingacute ischemic stroke, cerebral apoplexy, cerebral infarction, headtrauma, cerebral nerve cell death, Alzheimer disease, Parkinson disease,amyotrophic lateral sclerosis, Huntington disease, cerebral circulatorymetabolism disturbance, cerebral function disturbance, pain, spasm,schizophrenia, migraine, epilepsy, maniac-depressive psychosis, nervedegenerative diseases, cerebral ischemia, AIDS dementia complications,edema, anxiety disorder (generalized anxiety disorder) and diabeticneuropathy.

BACKGROUND OF THE INVENTION

In Japan, the number of patients with cerebral apoplexy is about 1.4million or more per year, and the medical expenses therefor areestimated to be about two billion yen. Cerebral apoplexy is the secondcause of death next to malignant tumor and is the biggest cause forbedridden man often suffering from severe secondary diseases. A key tothe treatment of cerebral apoplexy is to deal with the acute stage, andthe treatment at the acute stage influences the life and functionprognosis of the patient and significantly influences secondarydiseases.

For the purpose of improving blood stream, several drugs such as ozagrelsodium (thromboxane synthase inhibitor), argatroban (anti-thrombinagent) as an agent for treatment of chronic arterial occlusion, t-PA(alteplase: tissue plasminogen activator which should be used within 3hours after the onset) as thrombolytic agent etc. are now approved of,or in off lavel use.

In the treatment with these drugs, the following complicated techniquesand cautious judgement based on adequate knowledge and experience by amedical specialist are required.

(1) In the case of thrombus-type cerebral infarction, respiratorycontrol, blood pressure control and blood transfusion control are firstconducted.

(2) Blood gas and blood pressure are periodically measured.

(3) At the acute stage, reactive high blood pressure is observed, but ifcomplications in the heart and kidney are not observed, treatment fordecreasing blood pressure is not conducted.

(4) Then, in the early-acute stage case with no low absorption rangeobserved in CT, the thrombus-lytic agent “urokinase” is used.

(5) In the case where these agents are not applicable or in the casewhere 24 hours or more has elapsed after the onset, “ozagrel sodium” isadministered. Or “argatroban” is administered. However, argatroban isnot applicable to lacuna infarction.

(6) To prevent the development of cerebral edema, “glycerin” or“mannitol” is administered at a suitable dosage.

However, the therapeutic effects of the drugs used heretofore are notsatisfactory and further there is the danger that bleeding is oftenaccompanied by their pharmacological effect.

Accordingly, there is the problem that it is difficult for those exceptof skilled medical specialists to use these drugs.

JP 62-167762-A (EP 229623), JP 2-506694-A (WO 90/13539), DE 4404249, JP10-95758-A (EP 805147) etc. disclose compounds having piperazinecompounds being completely different in structure from theN,N-substituted cyclic amine compounds of the present invention.

BRIEF SUMMARY OF THE INVENTION

The present inventors sought a highly safe drug, which causes nobleeding, and is highly effective in treating and improving the acuteischemic stroke against which no useful drugs have been developed. Theinventors focused their attention on nerve-selective, voltage-dependentcalcium channel antagonist which directly acts on nerve cells to preventthe development of infarction volume, and they made extensive studiesthereon.

As a result, they have found that novel N,N-substituted cyclic aminecompounds having the following formula, or pharmacologically acceptablesalts thereof, possess an excellent action on inhibition of the death ofnerve cells and on protection of cerebral nerve cells, based oninhibitory action on P/Q type calcuim channels or N-type calciumchannels. These N,N-substituted cyclic amine compounds are superior insafety and can solve the problems described above, and the presentinvention has been thereby completed.

DETAILED DESCRIPTION OF THE INVENTION

The N,N-substituted cyclic amine compounds according to the presentinvention are represented by the following formula (VIII):

wherein

A represents an aryl group which may be substituted, a heteroaryl groupwhich may be substituted, an aralkyl group which may be substituted or aheteroaryl alkyl group which may be substituted;

E represents a group represented by the formula —CO— or a grouprepresented by the formula —CHOH—;

G represents an oxygen atom, a sulfur atom, and a group represented bythe formula —NR¹⁰— (wherein R¹⁰ represents a hydrogen atom, a loweralkyl group, a lower cycloalkyl, a lower acyl group or a lower alkylsulfonyl group), a group represented by the formula —CO—, a grouprepresented by —COO—, a group represented by the formula —OOC—, a grouprepresented by the formula —CONR¹¹— (wherein R¹¹ represents a hydrogenatom or a lower alkyl group), a group represented by the formula—NR¹²CO— (wherein R¹² represents a hydrogen atom or a lower alkylgroup), a group represented by the formula —SO—, a group represented bythe formula —SO₂—, a group represented by the formula —SONR¹³— (whereinR¹³ represents a hydrogen atom or a lower alkyl group) a grouprepresented by the formula —NR¹⁴SO— (wherein R¹⁴ represents a hydrogenatom or a lower alkyl group), a group represented by the formula—SO₂NR¹⁵— (wherein R¹⁵ represents a hydrogen atom or a lower alkylgroup), a group represented by the formula —NR¹⁶SO₂— (wherein R¹⁶represents a hydrogen atom or a lower alkyl group), a group representedby the formula >C═N—OR¹⁷ (wherein R¹⁷ represents a hydrogen atom or alower alkyl group), a group represented by the formula —NHCONH—, a grouprepresented by the formula —NHCSNH—, a group represented by the formula—C(═NH)NH—, a group represented by the formula —NHC(═NH)—, a grouprepresented by the formula —OCOS—, a group represented by the formula—SCOO—, a group represented by the formula —OCOO—, a group representedby the formula —NHCOO—, a group represented by the formula —OCONH—, agroup represented by the formula —CO(CH₂)_(s)O—, a group represented bythe formula —CHOH— or a group represented by the formula—CHOH(CH₂)_(s)O— (wherein s represents 0 or an integer of 1 to 6);

J represents an aryl group which may be substituted or a heteroarylgroup which may be substituted;

R¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a lowercycloalkyl group, a hydroxy lower alkyl group, a lower alkoxyalkylgroup, a cyano-lower alkyl group, a halogenated lower alkyl group, anoptionally N-substituted amino-lower alkyl group, a group represented bythe formula —NR¹⁸R¹⁹ (wherein R¹⁸ and R¹⁹ may be the same as ordifferent from each other and each represents a hydrogen atom or a loweralkyl group), an aralkyl group, a morpholinyl group, a thiomorpholinylgroup, a piperidyl group, a pyrrolidinyl group or a piperazinyl group;

Alk represents a linear or branched lower alkylene group; and

n, v, w, x and y are independent of each other and each represents 0 or1, and p represents 2 or 3.

The invention includes a pharmacologically acceptable salt of thecompound.

Herein, particular examples of the aryl group which may be substitutedare phenyl group, naphthyl group etc., or those further substituted withat least one of, for example, a halogen atom, a hydroxy group, a loweralkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, ahydroxy lower alkyl group, a halogenated lower alkyl group, a hydroxyiminoalkyl group, a cyano group, a nitro group, an optionallyN-substituted amino group, an optionally N-substituted carbamoyl group,an optionally N-substituted sulfamoyl group, a lower thioalkoxy group, alower acyl group, an aromatic acyl group etc.

Particular examples of the heteroaryl group which may be substituted arepyridyl group, pyrazinyl group, pyrimidinyl group, pyrrolyl group,imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group,quinazolinyl group, phthaladinyl group, quinoxalinyl group, cinnolynylgroup, furyl group, thienyl group, thiazolyl gorup etc., or thosefurther substituted.

Particular examples of the aralkyl group which may be substituted are alower alkyl group substituted with an aryl group, such as benzyl group,phenethyl group, phenylpropyl group, naphthylmethyl group, naphthylethylgroup, naphthylpropyl group etc., or that having the aryl group furthersubstituted.

Particular examples of the heteroaryl alkyl group which may besubstituted are a lower alkyl group substituted with a heteroaryl group,for example, pyridylmethyl group, pyrazinylmethyl group,pyrimidinylmethyl group, pyrrolylmethyl group, imidazolylmethyl group,pyrazolylmethyl group, quinolylmethyl group, isoquinolylmethyl group,furfuryl group, thienylmethyl group, thiazolylmethyl group etc., or thathaving the heteroaryl group further substituted.

Particular examples of the halogen atom are fluorine atom, chlorineatom, bromine atom or iodine atom.

Particular examples of the lower alkyl group are linear or branchedalkyl groups having 1 to 6 carbon atoms, such as methyl group, ethylgroup, n-propyl group, i-propyl group, n-butyl group, i-butyl group,t-butyl group, n-pentyl group, i-pentyl group, t-pentyl group, neopentylgroup, hexyl group etc.

Particular examples of the lower alkenyl group are groups derived fromlinear or branched alkenes having 2 to 6 carbon atoms, such as vinylgroup (CH₂═CH—), 1-propenyl group (CH₃CH═CH—), allyl group (CH₂═CHCH₂—),isopropenyl (CH₂═C(CH₃)—) etc.

Particular examples of the lower alkynyl group are groups derived fromlinear or branched alkynes having 2 to 6 carbon atoms, such as ethynylgroup, 1-propynyl group, 2-propynyl group etc.

Particular examples of the lower cycloalkyl group are cyclic alkylgroups having 3 to 8 carbon atoms such as cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group,cyclooctyl group etc.

Particular examples of the hydroxy lower alkyl group are a group havingone or more hydroxy groups bonded to the above-mentioned lower alkylgroup, such as a hydroxymethyl group, a hydroxyethyl group,2,3-dihydroxypropyl group etc.

Particular examples of the cyano-lower alkyl group are a group havingone or more cyano groups bonded to the above-mentioned lower alkylgroup, such as a cyanomethyl group, a cyanoethyl group, a cyanopropylgroup etc.

Particular examples of the halogenated lower alkyl group are a grouphaving one or more halogen atoms, which may be the same as or differentfrom each other, bonded to the above-mentioned lower alkyl group, suchas fluoromethyl group, difluoromethyl group, trifluoromethyl group,chloromethyl group, 1-fluoroethyl group, 2-fluoroethyl group,1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethylgroup, 2,2,2-trifluoroethyl group etc.

Particular examples of the lower alkoxy group are a group having theabove-mentioned lower alkyl group bonded to an oxygen atom,specifically, a linear or branched alkoxy group such as methoxy group,ethoxy group, n-propoxy group, i-propoxy, n-butoxy group, i-butoxygroup, t-butoxy group, pentyloxy group, hexyloxy group etc.

Particular examples of the lower acyl group are a linear or branchedacyl group derived from fatty acid having 1 to 6 carbon atoms, such asformyl group, acetyl group, propionyl group, butyryl group, isobutyrylgroup, valeryl group, isovaleryl group, pivaloyl group, hexanoyl groupetc.

Particular examples of the amino group which may be substituted are anamino which may be N-substituted by a lower alkyl group, a lower acylgroup, a lower alkyl sulfonyl group etc., and the case in which thenitrogen atom is part of a cyclic amine is included. Specifically, anamino group (—NH₂), methylamino group (—NHCH₃), dimethylamino group(—N(CH₃)₂), ethylamino group (—NHC₂H₅), diethylamino group (—N(C₂H₅)₂),methylethylamino group (—N(CH₃)C₂H₅), acetamide group (CH₃CONH—),propionamide group (C₂H₅CONH—), methanesulfonamide group (CH₃SO₂NH—),ethanesulfonamide group (C₂H₅SO₂NH—), pyrrolidinyl group, pyrazolinylgroup, piperidyl group, piperazinyl group, 4-morpholinyl group,4-thiomorpholinyl group etc. may be proposed.

Particular examples of the carbamoyl group which may be substituted area carbamoyl group which may be N-substituted by a lower alkyl groupetc., and the case in which the nitrogen atom is part of a cyclic amineis included. Specifically, carbamoyl group (—CONH₂), N-methylcarbamoylgroup (—CONHCH₃), N,N-dimethylcarbamoyl group (—CON(CH₃)₂),N-ethylcarbamoyl group (—CONHC₂H₅), N,N-diethylcarbamoyl group(—CON(C₂H₅)₂), N-methyl-N-ethylcarbamoyl group (—CON(CH₃)C₂H₅),1-pyrrolidinylcarbonyl group, 1-pyrazolylcarbonyl group,1-piperidylcarbonyl group, 1-piperazinylcarbonyl group,4-morpholinylcarbonyl group, 4-thiomorpholinylcarbonyl group etc. may beproposed.

Particular examples of the sulfamoyl group which may be substituted area sulfamoyl group which may be N-substituted by a lower alkyl groupetc., and the case in which the nitrogen atom is part of a cyclic amineis included. Specifically, sulfamoyl group (—SO₂NH₂), N-methylsulfamoylgroup (—SO₂NHCH₃), N,N-dimethylsulfamoyl group (—SO₂N(CH₃)₂),N-ethylsulfamoyl group (—SO₂NHC₂H₅), N,N-diethylsulfamoyl group(—SO₂N(C₂H₅)₂), N-methyl-N-ethylsulfamoyl group (—SO₂N(CH₃)C₂H₅),1-pyrrolidinylsulfonyl group, 1-pyrazolinylsulfonyl group,1-piperidylsulfonyl group, 1-piperazinylsulfonyl group,4-morpholinylsulfonyl group, 4-thiomorpholinylsulfonyl group etc. may beproposed.

Particular examples of the lower thioalkoxy group are a group having theabove-mentioned lower alkyl group bonded to a sulfur atom,suchasmethylthiogroup (—SCH₃), ethylthio group (—SC₂H₅) etc.

Particular examples of the lower alkylene group are a divalent groupderived from a linear or branched alkane having 1 to 6 carbon atoms,such as methylene group (—CH₂—), ethylene group (—CH₂CH₂—), ethylidenegroup (—CH(CH₃)—), trimethylene group (—CH₂CH₂CH₂—), isopropylidenegroup (—C(CH₃)₂—), propylene group (—CH(CH₃)CH₂—), tetramethylene group(—CH₂CH₂CH₂CH₂—), 1,2-butylene group (—CH(C₂H₅)CH₂—), 1,3-butylene group(—CH(CH₃)CH₂CH₂—), 2,3-butylene group (—CH(CH₃)CH(CH₃)—), isobutylenegroup (—C(CH₃)₂CH₂—) etc. Moreover, the bonding position (right-handedor left-handed) of the unsymmetrical alkylene group is not limited.

Particular examples of the lower alkoxy carbonyl group are a carbonylgroup substituted by the above-mentioned lower alkoxy group, such asmethoxy carbonyl group, ethoxy carbonyl group etc.

Particular examples of the lower thioalkoxy group are a group having theabove-mentioned lower alkyl group bonded to a sulfur atom, such asmethyl thio group, ethyl thio group, propyl thio group etc.

Particular examples of the lower alkyl sulfonyl group are a group havingthe above-mentioned lower alkyl group bonded to a sulfonyl group, suchas methane sulfonyl group, ethane sulfonyl group, propane sulfonyl groupetc.

When R²⁰ groups or R²¹ groups are bonded by themselves to form analicyclic ring, particular examples of this group are an alicycliccondensed phenyl group such as indanyl group, tetralinyl group etc., ora group in which the alicyclic group or phenyl group is furthersubstituted.

When R²⁰ groups or R²¹ groups are bonded by themselves to form a heteroring, particular examples of this ring are a hetero ring condensed withphenyl group, such as benzofuranyl group, chromanyl group, isochromanylgroup, indolynyl group, isoindolynyl group, teterhydroquinolyl group,tetrahydroisoquinolyl group, or groups in which the hetero ring orphenyl group is further substituted.

When R²⁰ groups or R²¹ groups are bonded by themselves to form analkylene dioxy group, particular examples of this group are methylenedioxy phenyl group, ethylene dioxy phenyl group, or groups in which thephenyl group is further substituted.

Herein, particular examples of the aryl group which may be substitutedare phenyl group, naphthyl group etc., or groups having these groupsfurther substituted.

Particular examples of the heteroaryl group which may be substituted arepyridyl group, pyrazinyl group, pyrimidinyl group, pyrrolyl group,imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group,quinazolinyl group, phthaladinyl group, quinoxalinyl group, cinnolynylgroup, furyl group, thienyl group, thiazolyl group etc., or groupshaving these groups further substituted.

Particular examples of the aralkyl group which may be substituted are alower alkyl group substituted with an aryl group, such as benzyl group,phenethyl group, phenyl propyl group, naphthyl methyl group, naphthylethyl group, naphthyl propyl group etc., or groups having the aryl groupfurther substituted.

Particular examples of the heteroaryl alkyl group which may besubstituted are a lower alkyl group substituted with a heteroaryl group,for example, pyridyl methyl group, pyrazinyl methyl group, pyrimidinylmethyl group, pyrrolyl methyl group, imidazolyl methyl group, pyrazolylmethyl group, quinolyl methyl group, isoquinolyl methyl group, furfurylgroup, thienyl methyl group, thiazolyl methyl group etc., or groupshaving the heteroaryl group further substituted.

Particular examples of the lower alkyl group are C₁ to C₆ alkyl groups,such as methyl group, ethyl group, n-propyl group, i-propyl group,n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl groupetc.

Particular examples of the lower cycloalkyl group are C₃ to C₈cycloalkyl groups, such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cycloctyl groupetc.

Herein, particular examples of the halogen atom are fluorine atom,chlorine atom, bromine atom or iodine atom.

Particular examples of the lower alkoxy group are a group having theabove-mentioned lower alkyl group bonded to an oxygen atom, such asmethoxy group, ethoxy group, propoxy group etc.

Particular examples of the amino group which may be substituted are anamino group or a group wherein 1 or 2 hydrogen atoms in the amino groupis substituted by lower alkyl group etc., such as methyl amino group,ethyl amino group, dimethyl amino group, diethyl amino group, methylethyl amino group etc.

Particular examples of the lower alkoxy carbonyl group are a carbonylgroup substituted by the above-mentioned lower alkoxy group, such asmethoxy carbonyl group, ethoxy carbonyl group etc.

Particular examples of the lower thioalkoxy group are a group having theabove-mentioned lower alkyl group bonded to a sulfur atom, such asmethyl thio group, ethyl thio group, propyl thio group etc.

Particular examples of the lower alkyl sulfonyl group are a group havingthe above-mentioned lower alkyl group bonded to a sulfonyl group, suchas methane sulfonyl group, ethane sulfonyl group, propane sulfonyl groupetc.

Particular examples of the lower acyl group are a group having theabove-mentioned lower alkyl group bonded to a carbonyl group, such asacetyl group, propionyl group, butyroyl group etc.

When R²⁰ groups or R²¹ groups are bonded to form an alicyclic ring,particular examples of this group are an alicyclic condensed phenylgroup such as indanyl group, tetralinyl group etc., or the group inwhich alicyclic group or phenyl group is further substituted.

When R²⁰ groups or R²¹ groups are bonded to form a hetero ring,particular examples of this ring are a hetero ring condensed with phenylgroup, such as benzofuranyl group, chromanyl group, isochromanyl group,indolynyl group, isoindolynyl group, teterhydroquinolyl group,tetrahydroisoquinolyl group, or groups in which the hetero ring orphenyl group is further substituted.

When R²⁰ groups or R²¹ groups are bonded to form an alkylene dioxygroup, particular examples of this group are methylene dioxy phenylgroup, ethylene dioxy phenyl group, or groups in which the phenyl groupis further substituted.

The invention includes as an embodiment an N,N-substituted cyclic aminecompound (I) represented by the following formula (I):

wherein

A represents an aryl group which may be substituted, a heteroaryl groupwhich may be substituted, an aralkyl group which may be substituted or aheteroaryl alkyl group which may be substituted;

E represents a group represented by the formula —CO— or a grouprepresented by the formula —CHOH—;

G represents an oxygen atom, a sulfur atom, and a group represented bythe formula —NR¹⁰— (wherein R¹⁰ represents a hydrogen atom, a loweralkyl group, a lower acyl group or a lower alkyl sulfonyl group), agroup represented by the formula —CO—, a group represented by —COO—, agroup represented by the formula —OOC—, a group represented by theformula —CONR¹¹— (wherein R¹¹ represents a hydrogen atom or a loweralkyl group) a group represented by the formula —NR¹²CO— (wherein R¹²represents a hydrogen atom or a lower alkyl group), a group representedby the formula —SO—, a group represented by the formula —SO₂—, a grouprepresented by the formula —SONR¹³— (wherein R¹³ represents a hydrogenatom or a lower alkyl group) a group represented by the formula —NR¹⁴SO—(wherein R¹⁴ represents a hydrogen atom or a lower alkyl group), a grouprepresented by the formula —SO₂NR¹⁵— (wherein R¹⁵ represents a hydrogenatom or a lower alkyl group), a group represented by the formula—NR¹⁶SO₂— (wherein R¹⁶ represents a hydrogen atom or a lower alkylgroup), a group represented by the formula >C═N—OR¹⁷ (wherein R¹⁷represents ahydrogen atom or a lower alkyl group), a group representedby the formula —NHCONH—, a group represented by the formula —NHCSNH—, agroup represented by the formula —C(═NH)NH—, a group represented by theformula —NHC (═NH)—, a group represented by the formula —OCOS—, a grouprepresented by the formula —SCOO—, a group represented by the formula—OCOO—, a group represented by the formula —NHCOO—, a group representedby the formula —OCONH—, a group represented by the formula—CO(CH₂)_(s)O—, a group represented by the formula —CHOH— or a grouprepresented by the formula —CHOH(CH₂)_(s)O— (wherein s is 0 or aninteger of 1 to 6);

J represents an aryl group which may be substituted or a heteroarylgroup which may be substituted;

R¹ represents a lower alkyl group, a lower cycloalkyl group, a grouprepresented by the formula —NR¹⁸R¹⁹ (wherein R¹⁸ and R¹⁹ may be the sameor different from each other and each represents a hydrogen atom or alower alkyl group), a morpholinyl group, a thiomorpholinyl group, apiperidyl group, a pyrrolidnyl group or a piperazinyl group;

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ may be the same or different from eachother and each represents a hydrogen atom or a lower alkyl group; and

m, o, q, and r may be the same or different from each other and eachrepresents 0 or an integer of 1 to 6, n is 0 or 1, and p is 2 or 3.

Next, the invention includes as an embodiment an N,N-substituted cyclicamine compound (II) represented by the following formula (II):

wherein A, E, G, J, R¹, m, n, o, p, q and r have the same meanings asdefined above.

Next, the invention includes as an embodiment an N,N-substituted cyclicamine compound (III) represented by the following formula (III):

wherein A, G, J, R¹, m, p and q have the same meanings as defined above.

Finally, the invention includes as an embodiment an N,N-substitutedcyclic amine compound (IV) represented by the following formula (IV):

wherein

R¹, m, p, and q have the same meanings as defined above;

R²⁰ and R¹² are the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, a hydroxy group, a mercaptogroup, a lower alkyl group, a lower alkoxy group, a hydroxymethyl group,a nitro group, an amino group which may be substituted, a cyano group, acarboxyl group, a lower alkoxy carbonyl group, a lower thioalkoxy group,a lower alkyl sulfonyl group, a lower acyl group, a halogenated loweralkyl group, an aryl group which may be substituted, a heteroaryl groupwhich may be substituted, an aryloxy group, an aralkyloxy group, a loweralkoxycarbonylalkoxy group or a hydroxy lower alkoxy group, and R²⁰groups or R²¹ groups may form an alicyclic group which may besubstituted, or a heterocyclic group or alkylene dioxy group which maybe substituted; and

j and t may be the same or different from each other and each represents0 or an integer of 1 to 5.

The N,N-substituted cyclic amine compounds (VIII) and those havingformulas (I) to (IV) according to the present invention contain 1 ormore asymmetric carbon atoms in the molecule, so their optical isomersor meso forms can exist, but the present invention is not limited. Thepresent invention encompasses any of the optical isomers, meso forms andracemates of these compounds. Further, these include not only anhydridesbut also hydrates and polymorphs.

When producing the optically active substances, optically activestarting materials can be used for asymmetric synthesis, or racematescan be optically resoluted by column chromatography or crystallization.

The pharmacologically acceptable salts in the present invention are notlimited insofar as they form salts with the N,N-substituted cyclic aminecompounds (VIII) and (I) to (IV) of the present invention, andparticular examples are inorganic acid addition salts such ashydrochloride, sulfate, nitrate, hydrobromate, hydriodate, perchlorate,phosphate etc., organic acid addition salts such as oxalate, maleate,fumarate, succinate etc., sulfonic acid addition salts such as methanesulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate,camphor sulfonate, and amino acid addition salts, among whichhydrochloride and oxalate are preferable.

More specific examples of the N,N-substituted amine compounds (VIII) and(I) to (IV) according to the present invention include the followingcompounds which are not intended to limit the present invention:

(1)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(2)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)propyl]piperazine

(3)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine

(4)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine

(5)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-fluorophenoxy)propyl]piperazine

(6) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine

(7) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-phenoxyethyl]piperazine

(8)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine

(9)1-[4-cyano-5-methyl-4-(4-methylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(10)1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(11)1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(12)1-[4-cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(13)1-[4-cyano-5-methyl-4-(4-hydroxymethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(14)1-[4-cyano-5-methyl-4-(4-hydroxyiminomethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(15)1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(16)1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(17)1-[4-cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(18)1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(19)1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(20)1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(21)1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(22)1-{[4-cyano-5-methyl-4-(2-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(23)1-{[4-cyano-5-methyl-4-(3-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(24)1-{[4-cyano-5-methyl-4-(4-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(25)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(26) 1-[(4-cyano-4-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(27) 1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(28) 1-[(4-cyano-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(29) 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(30)1-[(4-cyano-6-methyl-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(31)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-fluorophenoxy)ethyl]piperazine

(32)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

(33)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)pentyl]piperazine

(34)1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-fluorophenoxy)ethyl]piperazine

(35)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-difluorophenoxy)ethyl]piperazine

(36)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

(37)1-{[4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(38)1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(39)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine

(40)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine

(41)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine

(42)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine

(43)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminophenoxy)ethyl]piperazine

(44)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-acetamidophenoxy)ethyl]piperazine

(45)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophenoxy)ethyl]piperazine

(46)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanophenoxy)ethyl]piperazine

(47)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperazine

(48)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine

(49)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylthio)ethyl]piperazine

(50)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylsulfonyl)ethyl]piperazine

(51)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]piperazine

(52)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylamino]ethyl}piperazine

(53)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-acetylamino]ethyl}piperazine

(54)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methanesulfonylamino]ethyl}piperazine

(55)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

(56)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine

(57)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine

(58)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-isopropylamino)ethyl]piperazine

(59)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine

(60)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-fluorophenyl)propyl]piperazine

(61)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)acetyl]piperazine

(62)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine

(63)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine

(64)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoylamino)ethyl]piperazine

(65)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine

(66)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine

(67)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)sulfamoyl]ethyl}piperazine

(68)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylsulfamoyl]ethyl}piperazine

(69)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-fluorobenzenesulfonylamino)ethyl]piperazine

(70)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-fluorophenylthio)carbonyloxy]ethyl}piperazine

(71)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine

(72)1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl-4-[2-(4-fluorophenoxy)ethyl]piperazine

(73)1-(2-hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenoxy)ethyl]piperazine

(74)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzylphenoxy)ethyl]piperazine

(75)1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(76)1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(77)1-[4-cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(78)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-fluorophenoxy)ethyl]piperazine

(79)1-[(4-cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(80)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-fluorophenoxy)ethyl]piperazine

(81)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-fluorophenoxy)ethyl]piperazine

(82)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-fluorophenoxy)ethyl]piperazine

(83)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylanilino)ethyl]piperazine

(84)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylanilino)ethyl]piperazine

(85)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(4-isopropylanilino)ethyl]}piperazine

(86)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(3-isopropylanilino)ethyl]}piperazine

(87)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(2-isopropylanilino)ethyl]}piperazine

(88)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine

(89) Synthesis of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-quinolyloxy)ethyl]piperazine

(90)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-isoquinolyloxy)ethyl]piperazine

(91)1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(92)1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

(93)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

(94)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine

(95)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-quinolyloxy)ethyl]piperazine

(96)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine

(97)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine

(98)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-fluorophenoxy)ethyl]piperazine

(99)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-quinazolinyloxy)ethyl]piperazine

(100)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine

(101)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine

(102)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

(103)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

(104)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine

(105)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine

(106)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinyloxy)ethyl]piperazine

(107)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

(108)1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

(109)1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

(110)1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

(111)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine

(112)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenoxy]ethyl}piperazine

(113)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine

(114)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenylphenoxy)ethyl]piperazine

(115)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine

(116)1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-fluorophenoxy)ethyl]piperazineand

(117)1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine.

The compounds of the present invention have extremely high LD₅₀ andextremely high safety.

Among the above compounds of the present invention, for example,compounds of (1), (9), (10), (11), (20), (22), (23), (24), (36), (52),(75), (76), (79), (86), (88), (92), (95), (104), (107), (109) and (116)are preferable from the viewpoin of a pharmacological activity andsafety.

Next, the process for producing the N,N-substituted cyclic aminecompounds according to the present invention is not limited, and forexample it can be produced in the following manner.

(1) Production of N,N-Substituted Cylic Amine Compound (VIII) Where w>2and the Left Side-chain is Methyl Group

In this case, aldehyde compound (IX) and cyclic amine (X) can be reactedin the presence of a reducing agent according to conventional reductiveamination, for example a method described in shin Jikken Kagaku Koza14-III, page 1373, published by Maruzen K. K. This reaction is shown inthe following chemical scheme:

wherein A, E, G, J, Alk, R¹, v, n, w, x, y and p have the same meaningsas defined above.

Here in, the reducing agent is not limited insofar as it isconventionally used for reductive N-alkylation, and preferable examplesinclude sodium triacetoxy borohydride, sodium cyano borohydride, sodiumborohydride, lithium aluminum hydride etc.

(2) Production of N,N-Substituted Cylic Amine Compound (VIII) Where w>2and the Left Terminal is Methylene Group

In a method other than (1), the desired compound can be synthesized byadding active alkyl compound (XII) to cyclic amine (XI) in the presenceof a base. This reaction is shown in the following reaction scheme:

wherein A, E, G, J, Alk, R¹, v, n, w, x, y and p have the same meaningsas defined above. L is a leaving group such as halogen atom, methanesulfonyloxy group etc.

(3) Prodiirctin of N,N-Substituted Cyclic Amine Compound (I) Where o>2and Terminal R⁴═R⁵=H

In this case, aldehyde compound (V) and cyclic amine (VI) can be reactedin the presence of a reducing agent according to conventional reductiveamination, for example a method described in Shin Jikken Kagaku Koza14-III, page 1373, published by Maruzen K. K. This reaction is shown inthe following chemical scheme:

wherein A, E, G, J, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, n, o, p, qand r have the same meanings as defined above.

Herein, the reducing agent is not limited insofar as it isconventionally used for reductive N-alkylation, and preferable examplesinclude sodium triacetoxy borohydride, sodium cyano borohydride, sodiumborohydride, lithium aluminum hydride etc.

(4) Production of N,N-Substituted Cyclic Amine Compound (I) Where o>2and Terminal R⁴═R⁵=H

In a method other than (3), the desired compound can be synthesized byadding active alkyl compound (VII) to cyclic amine (VI) in the presenceof a base. This reaction is shown in the following reaction scheme:

wherein A, E, G, J, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, n, o, p, q,and r have the same meanings as defined above. L is a leaving group suchas halogen atom, methane sulfonyloxy group etc.

The administration form of the compounds of the present inventioninclude e.g. oral pharmaceutical preparations such as powder, finegranule, granule, tablet, coated tablet and capsule, externalapplication such as ointments, plaster and suppository, as well asinjection. For pharmaceutical composition manufacturing, conventionalpharmaceutical carriers can be used in a usual manner.

That is, for production of oral pharmaceutical composition,N,N-substituted cyclic amine compounds or pharmacologically acceptablesalts thereof and fillers, and as necessary binders, disintegrators,lubricants, coloring agents, taste and odor correctives etc. mixed andformed in a usual manner to form powder, fine granule, granule, tablet,coated tablet, capsule etc.

The fillers include e.g. milk sugar, corn starch, white sugar, glucose,mannitol, sorbit, crystalline cellulose, silicon dioxide etc.; thebinders include e.g. polyvinyl alcohol, polyvinyl ether, methylcellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymers,meglumine etc.; the disintegrators include e.g. starch, agar, gelatinpowder, crystalline cellulose, calcium carbonate, sodium bicarbonate,calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.;the lubricants include e.g. magnesium stearate, talc, polyethyleneglycol, silica, hardened vegetable oil; the coloring agents includethose approved to be added to pharmaceutical composition; and the tasteand odor correctives include cocoa powder, menthol, aromatic powder,peppermint oil, camphor, cinnamon powder. These tablets and granules maybe coated with sugar-coatings or any other materials as necessary.

For production of pharmaceutical composition for injection, pHadjustors, dissolution agents, isotonicity-imparting agents etc. and asnecessary dissolution assistants, stabilizers etc. are added to theN,N-substituted cyclic amine compounds or pharmacologically acceptablesalts thereof, to manufacture pharmaceutical composition in a usualmanner.

The method of producing the pharmaceutical composition for externalapplication is not limited, and these can be produced in a usual manner.That is, the base starting materials used in pharmaceuticalmanufacturing may be various starting materials conventionally used inpharmaceutical compositions, non-pharmaceutical compositions, cosmeticsetc.

Specifically, the base starting materials include e.g. raw materialssuch as animal and vegetable oil, mineral oil, ester oil, waxes, higheralcohols, fatty acids, silicon oil, surfactants, phospholipids,alcohols, polyols, water-soluble polymers, clays and minerals, purifiedwater etc., and as necessary, pH adjustors, antioxidants, chelatingagents, preservatives, anti-fungus agents, coloring agents, perfumesetc., but the base starting materials for external application accordingto the present invention are not limited to those enumerated above.Further, components having differentiation-inducing action, blood streampromoters, disinfectants, anti-inflammatory agents, cell activators,vitamins, amino acids, humectants, keratin-lytic agent etc. can also beincorporated. The amount of these base starting materials is usuallydetermined as an amount used in producing preparations for externalapplication.

In the present invention, the clinical dosage of the N,N-substitutedcyclic amine compounds or pharmacologically acceptable salts thereof isnot limited, and the dosage varies depending on conditions, severity,age, complications etc. and on the type of salt and administrationroute. This dosage is in the range of usually 0.01 to 1000 mg,preferably 0.1 to 500 mg, and more preferably 0.5 to 100 mg per day foran adult, and it is administered orally, intravenously, as suppositoryor percutaneously.

Hereinafter, the excellent pharmacological effects of the compounds ofthe present invention are mentioned as the effects of the invention.

For example, the following literatures describe that compounds having aninhibitory action on N type or P/Q type calcium channels can serve as anagent for inhibiting the death of nerve cells or for protecting cerebralnerve cells, an agent for treating or improving nervous diseases, anagent for treating or improving acute ischemic stroke, head trauma,death of nerve cells, Alzheimer disease, cerebral circulatory metabolismdisturbance, cerebral function disturbance or pain, an anti-spasm agent,an agent for treating or improving schizophrenia and an agent forpreventing, treating or improving migraine, epilepsy, maniac-depressivepsychosis, nerve degenerative diseases (Parkinson disease, Alzheimerdisease, amyotrophic lateral sclerosis, Huntington disease) cerebralischemia, epilepsy, head trauma, AIDS dementia complications, edema,anxiety disorder (generalized anxiety disorder) and diabetic neuropathy.

(1) Acute ischemia stroke: Annj. Rev. Physiol., 52, 543-559, 1990.

(2) Head trauma: SCRIP, No. 2203, 24, 1997.

(3) Ischemia—death of cerebral nerve cells: Advances in Pharmacology,22, 271-297, 1991.

(4) Alzheimer disease: Trends in Neuroscience, 16, 409, 1993.

(5) Cerebral circulatory metabolism disturbance: Nichiyakurishi, 85,323-328, 1985.

(6) Cerebral function disturbance: Acta Neurol. Scand., 78:2, 14-200,1998.

(7) Analgesic: Drug of the Future, 23 (2), 152-160, 1998.

(8) Cerebral ischemia, migraine, epilepsy, maniac-depressive psychosis:CasopisLekau Ceskych., 130 (22-23), 625-630, 1991.

(9) Nerve degenerative diseases (Parkinson disease, Alzheimer disease,amyotrophic lateral sclerosis, Huntington disease), cerebral ischemia,epilepsy, head trauma, and AIDS dementia complications: Revista deNeurologia., 24 (134), 1199-1209, 1996.

Further, for example, the following literatures describe that compoundshaving an inhibitory action on N type or P/Q type calcium channels canserve as an agent for preventing, treating or improving edema, anxietydisorder (generalized anxiety disorder), schizophrenia, diabeticneuropathy and migraine.

(10) Edema: Brain Research, 776, 140-145, 1997.

(11) Anxiety disorder (generalized anxiety disorder), schizophrenia:Jyunkanseigyo (Circulation Control), 14 (2), 139-145, 1993.

(12) Diabetic neuropathy: Shinkeinaika (Neurological Medicine), 50,423-428, 1999.

(13) Migraine: Neurology, 50 (4), 1105-1110, 1998.

Accordingly the invention provides a calcium antagonist comprising theN,N-substituted cyclic amine compounds or a pharmacologically acceptablesalt thereof; a nerve-selective calcium antagonist comprising theN,N-substituted cyclic amine compounds or a pharmacologically acceptablesalt thereof; an agent for preventing, treating and improving thediseases against which an inhibitory action on P/Q type calcium channelis effective, comprising the N,N-substituted cyclic amine compounds or apharmacologically acceptable salt thereof; an agent for preventing,treating and improving the diseases against which an inhibitory actionon N type calcium channel is effective, comprising the N,N-substitutedcyclic amine compounds or a pharmacologically acceptable salt thereof;an agent for inhibiting the death of nerve cells or for protecting brainnerve cells, comprising the N,N-substituted cyclic amine compounds or apharmacologically acceptable salt thereof; an agent for preventing,treating or improving a nerve disease, comprising the N,N-substitutedcyclic amine compounds or a pharmacologically acceptable salt thereofwherein the nerve cell disease may be one disease selected from thegroup consisting of acute ischemic stroke, cerebral apoplexy, cerebralinfarction, head trauma, cerebral nerve cell death, Alzheimer disease,Parkinson disease, amyotrophic lateral sclerosis, Huntington disease,cerebral circulatory metabolism disturbance, cerebral functiondisturbance, pain, spasm, schizophrenia, migraine, epilepsy,maniac-depressive psychosis, nerve degenerative diseases, cerebralischemia, AIDS dementia complications, edema, anxiety disorder(generalized anxiety disorder) and diabetic neuropathy; and a calciumantagonist composition comprising a pharmacologically effective amountof the N,N-substituted cyclic amine compounds or a pharmacologicallyacceptable salt thereof and a pharmacologically acceptable carrier.

Moreover the present invention provides a method of treating a diseaseagainst which calcium antagonism is effective, which comprisesadministering a pharmacologically effective amount of theN,N-substituted cyclic amine compounds or a pharmacologically acceptablesalt thereof to a patient suffering from the disease; and use of theN,N-substituted cyclic amine compounds or a pharmacologically acceptablesalt thereof for manufacturing calcium antagonist.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing effect of reducing infarct volume of thecompound of the present invention (i.v.) in a rat model with occlusionin the middle cerebral artery (represented by Mean±SE).

FIG. 2 is a graph showing effect of reducing infarct volume of thecompound of the present invention (i.v.) in a rat model with occlusionin the middle cerebral artery (represented by Mean±SE).

FIG. 3 is a graph showing effect of reducing infarct volume of controlcompound (i.v.) in a rat model with occlusion in the middle cerebralartery (represented by Mean±SE).

FIG. 4 is a graph showing antalgic effect of the compound of the presentinvention (i.v.) on mice in a formalin test (represented by Mean±SE)

FIG. 5 is a graph showing antalgic effect of the compound of the presentinvention (i.v.) on mice in a formalin test (represented by Mean±SE).

FIG. 6 is a graph showing antalgic effect of morphine (p.o.) on mice ina formalin test (represented by Mean±SE).

FIG. 7 is a graph showing antalgic effect of indomethacin (p.o.) on micein a formalin test (represented by Mean±SE).

FIG. 8 is a HPLC chart showing that the compound obtained in Example 1was optically resoluted by optically active column HPLC (the above(former) main peak shows the compound of Example 75 and the below(latter) shows the compound of Example 76).

PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 1 Measurement of Voltage-dependentCalcium Channel Activity by the use of a Fluorescent Pigment (fura 2)

(1) Relationship Between Model and Disease

At present, the “glutamic acid-Ca hypothesis” is regarded as the mostimportant as the mechanism of brain infarction (the death of nerve cellsdue to ischemia). That is, if cerebral blood stream is reduced,anaerobic glycolysis occurs and ATP in cerebral tissues is exhausted.Because of this energy exhaustion, an intracellular and extracellularion concentration gradient cannot be maintained to generatedepolarization. In pre-synapses, voltage-dependent calcium channels areactivated due to the depolarization, and excessive release of glutamicacid is induced. In post-synapses, voltage-dependent calcium channelsare activated due to the depolarization, and intracellular Ca²⁺ levelsare increased, while excessively released glutamic acid stimulatesglutamic acid receptors to increase intracellular Ca²⁺ levels. As aresult, a wide variety of Ca²⁺-dependent enzymes such as calpain andphospholipase are activated to induce the death of nerve cells. Out ofthis flowchart, the inflow of Ca²⁺ inpre-synapses can be evaluated inthis experiment system.

(2) Preparation of Cerebral Cortex Synaptosome

Cerebral cortex synaptosome was prepared in the following method inaccordance with Neuropharmacology, 32 (11), 1195-1202, 1993.

Cerebral cortexes were removed from cut rat brains and disrupted roughlywith scissors. These were introduced into a homogenizer, homogenized in0.3 M saccharose and centrifuged at 4° C. (1,500 g×10 min). Theresulting supernatant was further centrifuged at 4° C. (10,000 g×20min). The resulting precipitates were suspended in 0.3 M saccharose. Thesuspension was layered on 0.8 M saccharose and centrifuged (10,000 g×30min.). The resulting precipitates were suspended in solution A (118 mMNaCl, 4.6 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂, 1.2 mM Na₂HPO₄, 10 mMD-glucose, 20 mM HEPES-NaOH pH 7.4, 0.1% BSA) to give cerebral cortexsynaptosome.

(3) Inhibitory Action on Calcium Channels

4 μM fura 2/AM (Dojin Ltd.) was suspended in solution A to prepare aloading solution. To the synaptosome solution prepared in the methoddescribed above was added an equal volume of the loading solution, andthe mixture was incubated for 40 minutes at room temperature. Afterincubation, the loading solution was removed by centrifugation, and thesample was further washed twice with solution A. Solution A containingthe compound of the present invention was added thereto and incubatedfor 10 minutes at room temperature. {fraction (1/10)} volume of solutionB (122.6 mM KCl₂, 1 mM CaCl₂, 1 mM MgCl₂, 1.2 mM Na₂HPO₄, 10 mMD-glucose, 20 mM HEPES-NaOH pH 7.4, 0.1% BSA) was added thereto tostimulate the calcium channels. Intracellular calcium ion levels weredetermined by measurement at 2 wavelengths of 340 nm and 380 nm withARUGUS-FDSS (Hamamatsu Pothonics Co., Ltd.), and the IC₅₀ of eachcompound was determined.

As comparative and control compound, verapamil hydrochloride was used.

Example IC₅₀ (μM) 1 5.9 2 4 3 4.8 4 5.7 5 7.7 6 2.7 7 8.9 8 4.2 9 3.5 103.2 11 4.8 12 8.1 14 8.7 15 9.8 16 4.8 17 >16 19 6 20 5.5 22 5.4 23 4.324 3.9 25 9.7 27 4.6 28 7.2 29 4 30 2.9 31 9.3 32 6.2 33 3.4 34 3.8 355.2 36 3.4 37 2.7 38 4 39 9.6 40 10 43 13 45 4.6 46 16 47 13 48 8.4 494.8 51 7.5 52 3.8 56 16 59 12 60 10 61 11 62 8.8 63 7.4 65 >16 66 8.2 6710 68 8.7 69 9.2 70 3.8 71 >16 75 4.5 76 5.8 77 7.5 78 15 79 3.3 80 3.8Control >16 81 >16 82 5.0 83 13 84 6.0 85 16 86 4.3 87 >16 88 4.9 89 2.790 2.6 91 2.1 92 1.8 93 2.4 94 6.1 95 11 96 5.4 97 3.9 98 >16 99 >16100 >16 101 9.2 102 2.7 103 2.5 104 2.2 105 >16 106 7.0 107 4.1 108 3.3109 3.3 110 3.5 111 >16 112 >16 113 4.5 114 6.8 115 5.8 116 5.5 117 3.2118 6.4 119 7.7 120 4.1 121 6.8 122 12 Control: verapamil hydrochloride

PHARMACOLOGICAL TEST EXAMPLE 2 Inhibitory Activity on Glutamic AcidRelease

(1) Relationship Between Model and Disease

This experimental system is considered to be an experimental system inwhich the release of glutamic acid in pre-synapses in the flow-chart ofthe “glutamic acid-Ca hypothesis” can be evaluated.

(2) Preparation of Rat Cerebral Cortex Slices

Cerebral cortexes were isolated from SD strain male rats (8-week-old)and used to prepare 300 μm×300 μm slices by use of a slice chopper. Theprepared slices were incubated at 37° C. for 30 minutes in solution C(120 mM NaCl, 4 mM KCl, 10 mM MgSO₄, 16 mM NaHCO₃, 10 mM glucose, 1 mMNaH₂PO₄, 10 mM HEPES-NaOH pH 7.4) in the presence of 95% O₂/5% CO₂.Thereafter, solution C was exchanged with fresh one, followed by furtherincubation for 30 minutes.

(3) Glutamic Acid Release by Stimulation with High-conc. KCl

The cerebral cortex slices were incubated in a 24-wells plate for cellculture according to a multi-well method (Brain Res., 402, 255-263,1987), and the release of glutamic acid was induced with 50 mM KCl.Solution D (120 mM NaCl, 4 mM KCl, 1.2 mM CaCl₂, 1 mM MgSO₄, 16 mMNaHCO₃, 10 mM glucose, 1 mM NaH₂PO₄, 10 mM HEPES-NaOH pH 7.4) wasaerated with 95% O₂/5% CO₂ and kept at 37° C. and used in thisexperiment. 50 mM KCl containing the same total amount of K⁺ and Na⁺ wasprepared. Slices corresponding to 1 to 2 mg protein were placed on anupper cup provided with a mesh at the bottom, and 1.3 ml solution C or50 mM KCl solution was introduced into a lower well, and the upper cupwas transferred to a new well. 20 minutes before and 5 minutes afterreaction was intiated, the the test compound was added to solution D or50 mM KCl.

(4) Quantification Glutamic Acid

Glutamic acid was quantified by HPLC using fluorescent etor (Ex. 330 nmEm. 45 nm). The eluting solvent used was prepared by diluting 150 mlsodium citrate buffer for automatic amino acid analysis (Wako PureChemical Industries) 10-fold with distilled water, then adding MgCl₂thereto at the final concentration of 50 mM, and further diluting ittwice with acetonitrile. The flow rate was 2.0 ml/min. The column usedwas Asahipak (ES-502N Denko, K. K.). The glutamic acid was convertedinto a derivative by addition, to 50 μl sample, of 50 μl deriving agent(10 mg o-phthalaldehyde/500 μl MeOH, 10 μl b-mercaptopropionic acid,0.15 M sodium borate buffer pH 9.5, 100 μl) followed by stirring(Neuroscience Lett., 96, 202-206, 1989).

(5) Results

Examples IC₅₀ (μM) 1 3.5 9 2.4 10 2 11 3.8 20 1.9 22 4.1 23 2.5 24 2.436 4.2 52 2.9 75 2.9 76 3.9 79 5.9

Hereinafter, reduction of infarct volume in a rat model with occlusionin the middle cerebral artery, and the antalgic action on mice in aformalin test were tested with the compound of the present invention todemonstrate its in vivo effects of the invention.

PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 3 Effect (I) of Reducing InfarctVolume in a Rat Model with Occlusion in the Middle Cerebral Artery

(1) Background

Intracellular calcium ion plays an important role in exhibiting variouscellular functions. However, if intracellular calcium ion level israised excessively, cellular disturbance is induced (references, and soforth, 1 and 2). For example, nerve cell disturbance induced byexcitatory amino acids generated upon cerebral ischemia causes anexcessive increase in intracellular calcium ion level (3, 4). Uponoccurrence of local cerebral ischemia, the mechanism of maintainingmembrane potential is destroyed by the increased excitatory amino acids(3), and depolarization of the membrane is thereby induced (5), and theinflow of calcium ion into cells via voltage-dependent calcium channelsis increased (6, 7). From the foregoing, it is suggested that thehypothesis that the death of nerve cells is based on the excitatorytoxicity of excitatory amino acids is correlated with the hypothesisthat the death of nerve cells is based on the increase of intracellularcalcium ion, and that the activation of voltage-dependent calciumchannel contributes to induction of the death of nerve cells (8).

From electro-physiological and pharmacological studies, thevoltage-dependent calcium channels present in nerve cells are classifiedinto 6 subtypes (T, L, N, P, Q and R types) (9).

Among these, N, P and Q types play an important role in liberatingglutamic acid from synaptosomes in rat cerebral cortex (10, 11).

Accordingly, the protective effect of the typical compound of thepresent invention on nerve cells against disturbance induced uponoccurrence of local cerebral ischemia in a rat model with occlusion inthe middle cerebral artery was evaluated.

(2) Experimental Method

2-1) Preparation of Sample

The compound in Example 1 was selected as the typical example of thecompound of the present invention, and this sample was dissolved in5.28% mannitol to be adjusted to a dosage of 5 or 10 mg/kg/h just beforeuse. The concentration of the sample was calculated on the basis of theaverage weight of animals, as shown in the following example. Theaverage weight was determined by measuring the weights of all animals tobe used in the experiment.

Example) In the case of 10 mg/kg/h

Sample concentration=10 mgxaverage weight (kg)/volume (0.616 ml)administered per hour

2-2) Preparation of a Nylon Embolus

For occlusion in the middle cerebral artery, an embolus prepared fromnylon yarn of 4-0 monofilament (Ethicon, Inc., Somerville, N.J., USA)was used. The end of the nylon embolus was previously rounded withflame, and it was cut into fragments of 25 mm in length, and eachfragment was marked at a position 17 mm apart from the end with anoil-based felt pen.

2-3) Implantation of a Catheter for Intravenous Administration

Implantation of a catheter for intravenous administration (Atom venouscatheter 3Fr, Atom Medical Co., Ltd., Tokyo) was conducted underanesthesia with 70% laughing gas-2% halothane. The catheter filled withphysiological saline was inserted through the thigh vein in the leftleg.

2-4) Occlusion in the Middle Cerebral Artery

Occlusion in the middle cerebral artery was conducted in accordance withthe method of Longa et al. (12). Just after the catheter was implanted,the operation was conducted under anesthesia with 70% laughing gas-2%halothane. A rat was allowed to lie on the back and the cervical regionwas cut open under a stereoscopic microscope for operation, and the partwhere the common carotid artery at the right side branched into theexternal carotid artery and the internal carotid artery was confirmed.The external carotid artery was cut at the peripheral side, and thenylon embolus was inserted through the end of the cut external carotidartery into the internal carotid artery. The embolus was inserted untilthe position 17 mm apart from the end of the embolus reached the pointwhere the external carotid artery was joined to the internal carotidartery, and the embolus was fixed. To initiate blood stream again, thenylon embolus was removed 2 hours after the middle cerebral artery wasoccluded.

2-5) Selection of Animals with Ischemia Symptoms

Thirty minutes after the middle cerebral artery was occluded, each ratwas raised by holding the tail, and a rat clearly having hemiplegia inthe foreleg (paralysis in the foreleg at the opposite side to theproduced occlusion) was selected as an example where the middle cerebralartery was occluded to successfully cause ischemia conditions, and thisselected animal was subjected to the experiment.

2-6) Medium and Sample Administration

The rat showing hemiplegia 30 minutes after the middle cerebral arterywas occluded was placed in a cage with a unit for controlling bodytemperature, and the rat had a probe for monitoring body temperaturefixed to the rectum. Then, a syringe containing a medium or a sample wasattached to the catheter for intravenous administration, and half (0.31ml) of the dosage to be infused for 1 hour was intravenouslyadministered for 1 minute. Thereafter, the medium or the sample wasadministered continuously for 6 hours at a rate of 0.616 ml/h by the useof a syringe pump for infusion (Razel Scientific Instruments, Inc.,Stamford, Conn., USA). During administration and for 2 hours afteradministration was finished, the temperature of the rectum wasmaintained in the range of 37.0 to 38.5° C. in a system for controllingbody temperature. After the body temperature control was finished, theanimal was returned to the cage and maintained for 1 day in a breedingroom.

2-7) Measurement of Infarct Volume

Staining of Cerebral Slices with TTC

Twenty four hours after the middle cerebral artery was occluded, thehead was cut off from the rat and the brain was taken out. Blood adheredthereto was washed out in ice-cooled physiological saline. The brainfrom which the bulb for smelling had been removed was sliced at 2 mmintervals from the end (6 slices in total), and each slice was placed in2% TTC solution such that the rear of the brain faced upward. TTC wasdissolved in physiological saline when used. The sample was left at roomtemperature for at least 1 hour in the TTC solution and then measuredfor the infarct area.

Calculation of Infarct Volume

The upper face (the rear of the brain) of each slice was used forcalculation of the infarct area. An image of the cerebral slice wasinput into a computer (PM7500/100, Apple Japan, Tokyo) by the use of animage scanner (CCD color camera, Sankei, Tokyo). The cerebral cortexinfarct area in the image was determined using image analysis software(NIH image ver. 1.60, National Institutes of Health, USA). The infarctvolume from one animal was calculated as the total (mm³) of 6 slices bymultiplying the infarct area (mm²) in each slice by 2 (mm) which is thethickness of the slice.

2-8) Data Analysis

The infarct volume (mm³) in the cerebral cortex was expressed inmean±standard error. The statistical significance between the mediumcontrol group and each sample group was analyzed by Dunnett multiplecomparative test, and 5% of both the sides was regarded as level ofsignificance. The dosage reactivity was analyzed by regression analysis,and 5% of one side was regarded as level of significance.

(3) Results

After the middle cerebral artery was occluded for 2 hours by the nylonembolus, the nylon embolus was removed to initiate blood stream again,and 24 hours after the middle cerebral artery was occluded, the infarctvolume was measured. The results are shown in the table below and inFIG. 1 (*; p<0.05, **; p<0.01).

Infarct volume (mm³) in the cerebral cortex 24 hours after the middlecerebral artery was occluded

Mean Standard Error Number of Animals Control 224.06 14.41 14  5 mg/kg162.17 16.30 14 10 mg/kg 135.50 26.21 8

The infarct volume in the cerebral cortex in the control group was224.1±14.4 mm³. By intravenously administering the compound of thepresent invention at a dosage of 5 or 10 mg/kg/h 30 minutes after themiddle cerebral artery was occluded, the infarct volume in the cerebralcortex was reduced to 28% (162.2±16.3 mm³; p<0.05) and 40% (135.5±26.2mm³; p<0.01) respectively. As a result of regression analysis, it wasrecognized that the action of the compound of the present invention onreduction of infarct volume was dose-dependent.

(4) Summary

As described above, the compound of the present invention inhibits theinflow, induced by high KCl levels, of calcium ion into synaptosomes inthe rat cerebral cortex, and inhibits the liberation of glutamic acidfrom slices of the rat cerebral cortex. Further, in the presentexperiment, the compound of the present invention has a protectiveaction on nerve cells against disturbance caused by local cerebralischemia, and upon administration 30 minutes after generation ofischemia, the compound of the present invention exhibits the significanteffect of reducing the infarct volume, thus clarifying the effectivenessof the compound against human cerebral apoplexy by post treatment.

These results are also supported by the reports (13, 14) that SNX-111(CAS registration No. 107452-89-1) i.e. an inhibitor peptide for N-typecalcium channels serves for protection against the liberation ofglutamic acid from the cerebral cortex and against the subsequentdisturbance of nerve cells, in a rat model with local cerebral ischemia,and also by the report (15) that ω-agatoxin IVA i.e. an inhibitorpeptide for P/Q type channels has a protective action on nerve cells ina rat model with local cerebral ischemia.

(5) References

(1) Schanne, F. A. X., Kane, A. B., Young, E. E., Farber, J. L. Calciumdependence of toxic cell death: a final common pathway. Science 206:700-702 (1979).

(2) Kristian, T., Siesjo, B. K. Calcium in ischemic cell death. Stroke29: 705-718 (1998).

(3) Graham, S. H., Shiraisi, K., Panter, S. S., Simon, R. P., Faden, A.I. Changes in extracellular amino acid neurotransmitters produced byfocal cerebral ischemia. Neurosci. Lett. 110: 124-130 (1990).

(4) Rothman, S. M., Olney, J. W. Glutamate and the pathophysiology ofhypoxic-ischemic brain damage. Ann. Neurol. 19: 105-111 (1986).

(5) Siesjo, B. K., Bengtsson, F. Calciuminfluxes, calcium antagonists,and calcium-related pathology in brain ischemia, hypoglycemia, andspreading depression: A unifying hypothesis. J. Cereb. Blood Flow Metab.9: 127-140 (1989).

(6) Mayer, M. L., Miller, R. J. Excitatory amino acid receptors, secondmessengers and regulation of intracellular Ca²⁺ in mammalian neurons.Trends Pharmacol. Sci. 11: 254-260 (1990).

(7) Osuga, H., Hakim, A. M. Relationship between extracellular glutamateconcentration and voltage-sensitive calcium channel function in focalcerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 16: 629-636(1996).

(8) Choi, D. W. Calcium-mediated neurotoxicity: Relationship to specificchannel types and role in ischemic damage. Trends Neurosci. 11: 465-469(1988).

(9) Randall, A. D., Tsien, R. W. Pharmacological dessection of multipletypes of Ca²⁺ channel currents in rat cerebellar granule neurons. J.Neurosci. 15: 2995-3012 (1995).

(10) Turner, T. J., Dunlap, K. Pharmacological characterization ofpresynaptic calcium channels using subsecond biochemical measurements ofsynaptosomal neurosecretion. Neuropharmacology 34: 1469-1478 (1995).

(11) Maubecin, V. A., Sanchez, V. N., Rosato Siri, M. D., Cherksey, B.D., Sugimori, K., Llinas, R., Uchitel, O. D. Pharmacologicalcharacterization of the voltage-dependent Ca²⁺ channels present insynaptosomes from rat and chicken central nervous system. J. Neurochem.64: 2544-2551 (1995).

(12) Longa, E. Z., Weinstein, P. R., Carlson, S., Cummins, R. Reversiblemiddle cerebral artery occlusion without craniectomy in rats. Stroke 20:84-91 (1989).

(13) Bowersox, S. S., Singh, T., Luther, R. R. Selective blockade ofN-type voltage-sensitive calcium channels protects against brain injuryafter transient focal ischemia in rats, Brain Res. 747: 343-347 (1997).

(14) Takizawa, S., Matsushima, K., Fujita, H., Nanri, K., Ogawa, S.,Shinohara, Y. A selective N-type calcium channel antagonist reducesextracellular glutamate release and infarct volume in focal cerebralischemia. J. Cereb. Blood flow Metab. 15: 611-618 (1995).

(15) Asakura, K., Matsuo, Y., Kanemasa, T., Ninomiya, M. P/Q-type Ca²⁺channel blocker ω-agatoxin IVA protect against brain injury after focalischemia in rats. Brain Res. 7760: 140-145 (1997).

PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 4 Effect (II) of Reducing Infarctvolume in a Rat Model with Occlusion in the Middle Cerebral Artery

The typical example of the compound of the present invention (thecompound in Example 1) was compared with compounds disclosed in JP8-508037-A (WO 94/25469, U.S. Pat. No. 5,750,525), which have affinityfor AMPA receptors and is effective against cellular necrosis afterischemia in anoxia and hypocalcemia.

Hereinafter, only different features in the experimental method aredescribed.

(2) Experimental Method

2-1) Preparation of the Sample

a) Typical Example of the Compound of the Present Invention (TheCompound in Example 1)

The compound of the present invention was dissolved in physiologicalsaline to be adjusted to a dosage of 10 or 20 mg/kg/h just before use.

b) Control Compound

(JP 8-508037-A, Example 6)

Chemical name:{[3,4-Dihydro-7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-1-(2H)-quinoxalinyl]methyl}phosphonicacid (CAS registration number: 161605-73-8)

General name: MPQX, ZK200775

The control compound was dissolved in physiological saline to beadjusted to a dosage of 3 mg/kg/h just before use.

2-4) Occlusion in the Middle Cerebral Artery

Occlusion in the middle cerebral artery was conducted according to themethod described above. However, the middle cerebral artery waspermanently occluded without removing the nylon embolus.

2-6) Medium and Sample Administration

a) Compound of the Present Invention

Two hours after the middle cerebral artery was occluded, a syringecontaining the medium or the sample (10 or 20 mg/kg/h) was attached to acatheter for intravenous administration, and half (0.31 ml) of thedosage to be infused for 1 hour was intravenously administered for 1minute. Thereafter, the medium or the sample was administeredcontinuously for 6 hours at a rate of 0.616 ml/h by the use of a syringepump for infusion. During administration and for 2 hours afteradministration was finished, the temperature of the rectum wasmaintained in the range of 37.0 to 38.5° C. in a system for controllingbody temperature. After the body temperature control was finished, theanimal was returned to a cage and maintained for 1 day in a breedingroom.

b) Control Compound

Two hours after the middle cerebral artery was occluded, a syringecontaining the medium or the sample (3 mg/kg/h) was attached to acatheter for intravenous administration, and the medium or the samplewas administered continuously for 6 hours at a rate of 0.616 ml/h bymeans of the syringe pump for infusion. During administration and for 2hours after administration was finished, the temperature of the rectumwas maintained in the range of 37.0 to 38.5° C. in the system forcontrolling body temperature. After the body temperature control wasfinished, the animal was returned to a cage and maintained for 1 day ina breeding room.

(3) Results

The middle cerebral artery was permanently occluded by the nylonembolus, and the infarct volume was measured 24 hours after theocclusion was conducted.

a) Compound of the Present Invention

The infarct volume in the cerebral cortex from the control group was307.2±13.3 mm (n=7). As a result of intravenous administration of thecompound of the present invention at a dosage of 10 or 20 mg/kg/h twohours after the middle cerebral artery was occluded, the infarct volumein the cerebral cortex was reduced to 260.7±13.1 mm³ (n=8) and215.4±21.3 mm³ (n=7) respectively in a dose-dependent manner, and theinfarct volume in the 20 mg/kg/h administration group was statisticallysignificantly lower (p<0.01) than that of the control group. The degreesof reduction of the infarct volume by the compound of the presentinvention at dosages of 10 and 20 mg/kg/h were 15% and 30% respectively.

The results are shown in the table below and in FIG. 2. Infarct volume(mm³) in the cerebral cortex 24 hours after the middle cerebral arterywas occluded

Mean Standard Error Number of Animals Control 307.2 13.3 7 10 mg/kg260.7 13.1 8 20 mg/kg 215.4 21.3 7

b) Control Group

The infarct volume in the cerebral cortex from the control group was294.9±12.6 mm³ (n=9). Although the control compound was intravenouslyadministered at a dosage of 3 mg/kg/h two hours after the middlecerebral artery was occluded, the infarct volume in the cerebral cortexwas 284.9±10.9 mm³ (n=11), so there was no difference from the controlgroup.

The results are shown in the table below and in FIG. 3. Infarct volume(mm³) in the cerebral cortex 24 hours after the middle cerebral arterywas occluded

Mean Standard Error Number of Animals Control 294.9 12.6 9 3 mg/kg 284.910.9 11

From the results described above, it is evident that the compound of thepresent invention has the superior effect to that of the controlcompound.

PHARMACOLOGICAL EXPERIMENT EXAMPLE 5 Antalgic Effect (I) on Mice in aFormalin Test

(1) Background

N-type calcium channel that is one of nerve-specific calcium channels isinhibited selectively by a low-molecular peptide SNX-111. In a formalintest as one of analgesic tests, it is reported that SNX-111 has anantalgic action when administered into spinal cord (1, 2).

The antalgic action of the typical example of the compound of thepresent invention (Example 1) when intravenously administered wasexamined in the formalin test using mice (3).

(2) Method

2-1) Experimental Animals

ddy Mice (male, 4-week-old) purchased from Nippon SLC Ltd. were used inthe experiment.

The mice were maintained preliminarily for 4 days (conditions: roomtemperature, 23±1° C.; humidity, 55±5%; a cycle of bright and darkconditions at 12-hour intervals) A group consisting of about 20 animalswas accommodated and maintained in a 20-mouse polycarbonate cage inwhich wood chip bedding (white flakes) (Charles River Co., Ltd., Tokyo)were placed. In the morning of the day on which the experiment wasconducted, the cage was transferred to a laboratory (room temperature,23° C.; humidity, 35%).

The animals were satiated with MR (Oriental Yeast Co., Ltd.) and freewatered with tap water

2-2) Test Compound

As the typical example of the compound of the present invention, thecompound in Example 1 was used as the test compound.

2-3) Preparation of the Sample

20.4 mg of the test compound was weighed, and 10.2 ml of 5.28% mannitolwas added thereto to prepare 2 mg/ml (20 mg/kg) solution. Then, 3.8 mlof 5.28% mannitol was added to 3.8 ml of the 2 mg/ml solution to prepare1 mg/ml (10 mg/kg) solution. Finally, 2.5 ml of 5.28% mannitol was addedto 2.5 ml of the 1 mg/ml solution to prepare 0.5 mg/ml (5 mg/kg)solution. This test compound was weighed and prepared on the day whenthe experiment was conducted.

2-4) Preparation of the Reagent

30 μl of commercial 35.0 to 38.0% formaldehyde was added to 970 μlphysiological saline. The resulting solution was used as 3% formalin.Because the indicated purity of this commercial formaldehyde is 35.0 to38.0%, the 3% formalin presently prepared and used is accurately 2.84 to3.08% formalin.

2-5) Grouping, Number of Animals, and Dosage

The treatment group in this test consisted of 4 groups in total, thatis, a control group, a 5 mg/kg test compound administration group, a 10mg/kg administration group, and a 20 mg/kg administration group, andeach group consisted of 5 animals.

The control group was given 0.1 ml of 5.28% mannitol per 10 g of thebody weight. The test compound was administered at each concentration(0.5 mg/ml, 1 mg/ml, and 2 mg/ml) in an volume of 0.1 ml per 10 g of thebody weight into the 5 mg/kg group, 10 mg/kg group and 20 mg/kg group,respectively.

2-6) Test Method

5.28% mannitol was administered via the tail vein into each group giventhe compound of the present invention or into the control group, and theanimals were placed in a transparent plastic observation cage. 5 minuteslater, 20 μl of 3% formalin was subcutaneously administered into thebottom of the left hind leg of each mouse. The duration of the behaviorof mouse's licking the left hind leg after administration of formalinwas measured for 5 minutes and used as an indication of pain. Theduration was expressed in second.

2-7) Statistical Test

In the significant test, parametric one-way layout analysis of variancewas conducted and then Dunnet-type multiple comparison was made (*:0.01<p<0.05, **: p<0.01, vs. the control group). For the test, astatistical analysis assistant system with SAS 6.12 (SAS Institute JapanLtd., Tokyo) integrated in it was used.

(3) Results

The effect of the compound of the present invention in the formalin testwas expressed in terms of average left hind leg-licking time (sec.) andstandard error (see FIG. 4).

Mean Standard Error Number of Animals Control 91.4 14.5 5  5 mg/kg 49.46.8 5 10 mg/kg 23.6 7.9 5 20 mg/kg 2.2 2.2 5

As is evident from the above results, the groups given the compound ofthe present invention at dosages 5 mg/kg, 10 mg/kg and 20 mg/kgindicated a statistically significant reduction in licking time ascompared to that of the control group.

Similar to N-type calcium channel inhibitor SNX-111, the compound of thepresent invention i.e. a nerve-specific calcium channel inhibitorexhibits an antalgic action in the formalin test, so it is evident thatthe compound of the present invention is useful as an agent for treatingand improving acute pain.

(4) References

(1) Annika B. Malmberg, and Tony L. Yaksh (1994) Voltage-SensitiveCalcium Channels in Spinal Nociceptive Processing: Blockade of N- andP-Type Channels Inhibits Formalin-Induced Nociception. The Journal ofNeuroscience 14 (8): 4882-4890.

(2) S. Scott Bowersox, Theresa Gadbois, Tejinder Singh, Mark Pettus,Yong-Xiang Wang and Robert R. Luther (1996) Selective N-type NeuronalVoltage-Sensitive Calcium Channel Blocker, SNX-111, Produces SpinalAntinociception in Rat Models of Acute, Persistent and Neuropathic Pain.The Journal of pharmacology and Experimental Therapeutics 279 (3):1243-1249.

(3) Hunskaar S, Fasmer O B and Hole K (1985) Formalin test in mice, auseful technique for evaluating mild analgesics. Journal of NeuroscienceMethods 14 (1): 69-76.

PHARMACOLOGICAL EXPERIMENT EXAMPLE 6 Antalgic Effect (II) on Mice in aFormalin Test

The typical example of the compound of the present invention (thecompound in Example 1) was compared with morphine and indomethacin inthe same manner as in Pharmacological Experimental Example 5 above.

Hereinafter, only different features in the experimental method aredescribed.

(2) Experimental Method

2-1) Preparation of the Sample

a) Typical Example of the Compound of the Present Invention (theCompound in Example 1)

20.4 mg of the compound of the present invention was weighed, and 10.2ml of 5.28% mannitol was added thereto to prepare 2 mg/ml (20 mg/kg)solution. Then, 3.8 ml of 5.28% mannitol was added to 3.8 ml of the 2mg/ml solution to prepare 1 mg/ml (10 mg/kg) solution. Finally, 2.5 mlof 5.28% mannitol was added to 2.5 ml of the 1 mg/ml solution to prepare0.5 mg/ml (5 mg/kg) solution. The test compound was weighed and preparedon the day when the experiment was conducted.

b) Control Compounds

b-1) Morphine 17.0 mg of morphine purchased as a reagent was weighed,and 5.67 ml physiological saline was added thereto to form 3 mg/ml (30mg/kg) solution. Then, 2.6 ml physiological saline was added to 1.3 mlof the 3 mg/ml solution to prepare 1 mg/ml (10 mg/kg) solution. Finally,2.1 ml physiological saline was added to 0.9 ml of the 1 mg/ml solutionto prepare 0.3 mg/ml (3 mg/kg) solution. The test compound was weighedand prepared on the day when the experiment was conducted.

b-2) Indomethacin

12.9 mg of indomethacin purchased as a reagent was weighed, and 12.9 mlof 0.5% methyl cellulose (MC) was added thereto to form 1 mg/ml (10mg/kg) suspension. Then, 2.24 ml of 0.5% MC was added to 0.96 ml of the1 mg/ml suspension to prepare 0.3 mg/ml (3 mg/kg) suspension. Finally,1.6 ml of 0.5% MC was added to 0.8 ml of the 0.3 mg/ml suspension toprepare 0.1 mg/ml (1 mg/kg) suspension. The test compound was weighedand prepared on the day when the experiment was conducted.

2-5) Grouping, Number of Animals, and Dosage

a) Compound of the Present Invention

The treatment group by the compound of the present invention consistedof 4 groups in total, that is, a control group, a 5 mg/kg compoundadministration group, a 10 mg/kg compound administration group, and a 20mg/kg compound administration group, and each group consisted of 5animals.

The control group was given 0.1 ml of 5.28% mannitol per 10 g of thebody weight via the tail vein. The compound of the present invention wasadministered via the tail vein at each concentration (0.5 mg/ml, 1mg/ml, and 2 mg/ml) in an volume of 0.1 ml per 10 g of the body weightinto the 5 mg/kg group, 10 mg/kg group and 20 mg/kg group, respectively.

b-1) Morphine

The treatment group by morphine consisted of 4 groups in total, that is,a control group, a 3 mg/kg morphine administration group, a 10 mg/kgmorphine administration group, and a 30 mg/kg morphine administrationgroup, and each group consisted of 5 animals.

The control group was orally given 0.1 ml of physiological saline per 10g of the body weight. Morphine was orally administered at eachconcentration (0.3 mg/ml, 1 mg/ml, and 3 mg/ml) in a volume of 0.1 mlper 10 g of the body weight into the 3 mg/kg group, 10 mg/kg group and30 mg/kg group, respectively.

b-2) Indomethacin

The treatment group by indomethacin consisted of 4 groups in total, thatis, a control group, a 1 mg/kg indomethacin administration group, a 3mg/kg indomethacin administration group, and a 10 mg/kg indomethacinadministration group, and each group consisted of 5 animals.

The control group was orally given 0.1 ml of 0.5% MC per 10 g of thebody weight. Indomethacin was orally administered at each concentration(0.1 mg/ml, 0.3 mg/l, and 1 mg/ml) in a volume of 0.1 ml per 10 g of thebody weight into the 1 mg/kg group, 3 mg/kg group and 10 mg/kg group,respectively.

2-6) Test Method

a) Compound of the Present Invention

5.28% mannitol was administered via the tail vein into each group giventhe compound of the present invention or into the control group, and theanimals were placed in a transparent plastic observation cage. 5 minuteslater, 20 μl of 3% formalin was subcutaneously administered into thebottom of the left hind leg of each mouse. The duration of the behaviorof mouse's licking the left hind leg after administration of formalinwas measured for 5 minutes and used as an indication of pain. Theduration was expressed in second.

b-1) Morphine

Physiological saline was orally administered into each morphine group orthe control group, and the animals were placed in a transparent plasticobservation cage. 30 minutes later, 20 μl of 3% formalin wassubcutaneously administered into the bottom of the left hind leg of eachmouse. The subsequent steps are the same as in the test method of thecompound of the present invention.

b-2) Indomethacin

0.5% MC was orally administered into each indomethacin group or thecontrol group, and the animals were placed in a transparent plasticobservation cage. 90 minutes later, 20 μl of 3% formalin wassubcutaneously administered into the bottom of the left hind leg of eachmouse. The subsequent steps are the same as in the test method of thecompound of the present invention.

(3) Results

The effect of the compound of the present invention in the formalin testwas expressed in terms of average left hind leg-licking time (sec.) andstandard error, as follows.

a) Action of the Compound of the Present Invention on the Formalin Test(see FIG. 5).

Mean Standard Error Number of Animals Control 91.4 14.5 5  5 mg/kg 49.46.8 5 10 mg/kg 23.6 7.9 5 20 mg/kg 2.2 2.2 5

b-1) Action of Morphine on the Formalin Test (see FIG. 6).

Mean Standard Error Number of Animals Control 64.0 4.9 5  3 mg/kg 68.24.0 5 10 mg/kg 58.0 5.6 5 30 mg/kg 29.6 6.2 5

b-2) Action of Indomethacin on the Formalin Test (see FIG. 7).

Mean Standard Error Number of Animals Control 61.4 10.4 5  1 mg/kg 87.813.2 5  3 mg/kg 75.8 9.8 5 10 mg/kg 84.0 15.0 5

From the above experimental results, it is evident that indomethacindoes not have any effect, while the compound of the present inventionhas an excellent effect similar to that of morphine.

Hereinafter, Preparatory Examples of the starting materials in thepresent invention are specifically described below, but aldehydecompound and piperazine compound, such as2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile etc. can be synthesizedaccording to the following literatures:

(1) Compt. Rend., 256, 702 (1963).

(2) Compt. Rend., 256, 2632 (1963)

(3) Collect. Czech. Chem. Commun., 57, 1967 (1992).

PREPARATORY EXAMPLES Preparatory Example 1 Synthesis of1-[2-(4-Fluorophenoxy)ethyl]piperazine

1-Benzyl piperazine (8.3 g) and 2-(4-fluorophenoxy)ethyl bromide (10.3g) were dissolved in acetonitrile (100 ml), and Potassium carbonate(6.51 g) was added thereto, and the mixture was stirred overnight at 70to 80° C. The organic layer was partitioned by adding aqueous saturatedsodium bicarbonate and ethyl acetate, washed with water and brine, driedover sodium sulfate anhydrous, and evaporated. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate system) togive a colorless oil (12.3 g). The resulting colorless oil (12.3 g) wasdissolved in methanol (120 ml), and 10% palladium hydroxide/carbon wasadded thereto followed by overnight stirring in a hydrogen atmosphere.The reaction solution was filtered and evaporated, whereby the titlecompound (7.7 g, 73%) was obtained as a pale yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.55 (br, 4H), 2.78 (t, J=6 Hz, 2H),2.92 (br-t, J=4.8 Hz, 4H), 4.07 (t, J=6 Hz, 2H), 6.81-6.88 (m, 2H),6.93-7.00 (m, 2H).

Preparatory Example 2 Synthesis of 1-(2-Phenoxyethyl)piperazine

Piperazine (2.15 g) and 2-phenoxyethyl bromide (1.00 g) were dissolvedin tetrahydrofuran (30 ml), and the mixture was stirred at 40 to 60° C.for 36 hours. The reaction solution was evaporated, and aqueoussaturated sodium bicarbonate and diethyl ether were added to theresidue, and the aqueous layer was partitioned. Methylene chloride wasadded to the aqueous layer, and the organic layer was partitioned. Theorganic layer was dried over sodium sulfate anhydrous and evaporated,whereby the title compound (664 mg, 65%) was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.56 (br, 4H), 2.80 (t, J=6 Hz, 2H),2.92 (br-t, J=4.8 Hz, 4H), 4.12 (t, J=6 Hz, 2H), 6.88-6.98 (m, 3H),7.26-7.32 (m, 2H).

Preparatory Example 3 Synthesis of1-[2-(4-Fluorophenoxy)propyl]piperazine

1-Formyl piperazine (2.8 g) and 2-(4-fluorophenoxy)propyl chloride (4.7g) were dissolved in dimethylformamide (60 ml), and sodium iodide (3.2g) and triethylamine (4.4 ml) were added thereto, and the mixture wasstirred overnight at 50 to 70° C. The organic layer was partitioned byadding water and ethyl acetate, washed with brine, dried over sodiumsulfate anhydrous, and evaporated. The residue was purified byCromatorex NH silica gel column chromatography (ethyl acetate). Theresulting yellow oil (12.3 g) was dissolved in methanol (20 ml), and 5Naqueous sodium hydroxide (10 ml) was added thereto and then stirred for1 hour under reflux. The reaction mixture was evaporated, then theorganic layer was partitioned by adding water and ethyl acetate, washedwith brine, and dried over sodium sulfate anhydrous. The residueobtained by evaporation was purified by Cromatorex NH silica gel columnchromatography (ethyl acetate/methanol system), whereby the titlecompound (2.2 g, 38%) was obtained as a pale yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.93 (quintet, 7.2 Hz, 2H), 2.41 (br,4H), 2.47 (t, J=7.2 Hz, 2H), 2.87 (br-t, J=5.0 Hz, 4H), 3.94 (t, J=7.2Hz, 2H), 6.79-6.85 (m, 2H), 6.90-6.97 (m, 2H).

Preparatory Example 4 Synthesis of 1-(4-Phenoxybutyl)piperazine

tert-Butyl-1-piperazine carboxylate (1.0 g) and 4-phenoxybutyl chloride(991 mg) were dissolved in acetonitrile (50 ml), and triethylamine (1.5ml) and sodium iodide (160 mg) were added thereto, and the mixture wasstirred overnight at 50 to 70° C. After concentration, the organic layerwas partitioned by adding water and ethyl acetate, washed with brine,dried over sodium sulfate anhydrous, and evaporated. The resultingresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system) to give a colorless oil (222 mg). Thiscolorless oil (222 mg) was dissolved in dichloromethane (10 ml), andtrifluoroacetic acid (1 ml) was added thereto, and the mixture wasstirred overnight at room temperature. The organic layer was partitionedby adding aqueous saturated sodium bicarbonate and dichloromethane tothe reaction mixture and dried over sodium sulfate anhydrous. Theresidue was evaporated, whereby the title compound (190 mg, 15%) wasobtained as a pale yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.63-1.72 (m, 2H), 1.76-1.86 (m, 2H),2.38-2.43 (m, 2H), 2.43-2.52 (br, 4H), 2.92-2.98 (m, 4H), 3.96-4.00 (m,2H), 6.87-6.96 (m, 3H), 7.25-7.30 (m, 2H).

Further, the following compounds were synthesized according toPreparatory Examples 1 to 4.

Preparatory Example 5 1-[2-(4-Florophenoxy)ethyl]piperazine

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.70-1.82 (m, 3H), 2.78-2.88 (m, 4H),2.90-3.00 (m, 6H), 4.03 (t, J=6 Hz), 6.81-6.87 (m, 2H), 6.93-7.00 (m,2H).

Preparatory Example 6 1-[2-(4-Nitrophenoxy)ethyl]piperazine

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.35 (br-s, 4H), 2.62 (t, J=5.8 Hz,2H), 2.65-2.75 (m, 4H), 4.00 (t, J=5.8 Hz, 2H), 6.76 (d, J=9.2 Hz, 2H),7.95 (d, J=9.2 Hz, 2H).

Similarly, 1-[4-(phenoxy)butyl]piperazine was also obtained.

Hereinafter, the present invention is described in more detail byreference to Examples, which however are not intended to limit thepresent invention.

EXAMPLES Example 1 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

2-(1-Methylethyl)-5-oxo-2-phenyl pentane nitrile (100 mg),1-[2-(4-fluorophenyl)ethyl]piperazine (104 mg) and acetic acid (0.13 ml)were dissolved in dichloromethane (8.0 ml), and sodium triacetoxyborohydride (196 mg) was added thereto, and the mixture was stirredovernight at room temperature. The organic layer was partitioned byadding aqueous saturated sodium bicarbonate and dichloromethane, washedwith water, and dried over sodium sulfate anhydrous. The residueobtained by evaporation was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(168 mg, 86%) as a colorless oil. 4 N hydrogen chloride/ethyl acetatesolution was added to a methanol solution containing this free compound(168 mg). After stirred for 10 minutes, the solvent was evaporated,whereby the hydrochloride (190 mg) of the title compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.17 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.88 (dt, J=4.4 Hz, 12.4Hz, 1H), 2.06-2.19 (m, 2H), 2.24-2.30 (m, 2H), 2.30-2.43 (m, 4H),2.46-2.62 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H),6.80-6.85 (m, 2H), 6.91-6.99 (m, 2H), 7.25-7.32 (m, 1H), 7.32-7.40 (m,4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.22-1.34 (m, 1H), 1.58-1.62 (m, 1H), 2.06-2.30 (m, 3H),3.00-3.25 (m, 2H), 3.30-3.80 (m, 10H), 4.36 (br-s, 2H), 6.98-7.07 (m,2H), 7.11-7.20 (m, 2H), 7.32-7.40 (m, 1H), 7.40-7.50 (m, 4H).

ESI-Mass; 424 (MH+).

Example 2 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)propyl]piperazine

The title compound (196 mg, 99%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (100 mg) and1-[3-(4-fluorophenyl)propyl]piperazine (111 mg) in the same manner as inExample 1. This free compound (194 mg) was treated in the same manner asin Example 1 to give the hydrochloride (196 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.19 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.84-2.00 (m, 3H), 2.07-2.18 (m, 2H),2.23-2.55 (m, 13H), 3.92-3.99 (m, 2H), 6.79-6.85 (m, 2H), 6.91-6.99 (m,2H), 7.25-7.32 (m, 1H), 7.32-7.40 (m, 4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.22-1.34 (m, 1H), 1.56-1.72 (m, 1H), 2.06-2.28 (m, 5H),3.00-3.95 (m, 12H), 4.00-4.10 (m, 2H), 6.92-7.01 (m, 2H), 7.10-7.18 (m,2H), 7.33-7.42 (m, 1H), 7.42-7.48 (m, 4H).

ESI-Mass; 438 (MH+).

Example 3 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (166 mg, 82%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (100 mg) and1-[2-(4-fluorophenyl)ethyl]homopiperazine (111 mg) in the same manner asin Example 1. This free compound (166 mg) was treated in the same manneras in Example 1 to give the hydrochloride (169 mg) of the titlecompound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.02-1.16 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.46-1.57 (m, 1H), 1.70-1.77 (m, 2H), 1.88(dt, J=4.4 Hz, 12.4 Hz, 1H), 2.06-2.19 (m, 2H), 2.33-2.45 (m, 2H),2.53-2.57 (m, 4H), 2.74-2.81 (m, 4H), 2.92 (t, J=6.2 Hz, 2H), 4.00 (t,J=6.2 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-7.00 (m, 2H), 7.26-7.33 (m, 1H),7.33-7.40 (m, 4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.18-1.22 (m, 1H), 1.55-1.70 (m, 1H), 2.06-2.28 (m, 5H),3.00-3.20 (m, 2H), 3.20-3.70 (m, 8H), 3.70-3.96 (m, 2H), 4.30-4.40 (m,2H), 6.98-7.05 (m, 2H), 7.11-7.20 (m, 2H), 7.33-7.40 (m, 1H), 7.40-7.50(m, 4H).

ESI-Mass; 438 (MH+).

Example 4 Synthesis of1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine

The title compound (85 mg, 57%) was obtained as a colorless oil from2-(1-methylethyl)-4-oxo-2-phenyl butyronitrile (70 mg) and1-[2-(4-fluorophenyl)ethyl]homopiperazine (83 mg) in the same manner asin Example 1. This free compound (85 mg) was treated in the same manneras in Example 1 to give the hydrochloride (88 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.8Hz, 3H), 1.70-1.77 (m, 2H), 1.99-2.15 (m, 3H), 2.30-2.37 (m, 1H),2.45-2.90 (m, 9H), 2.90 (t, J=6.2 Hz, 2H), 3.99 (t, J=6.2 Hz, 2H),6.80-6.86 (m, 2H), 6.93-7.00 (m, 2H), 7.28-7.33 (m, 1H), 7.33-7.40 (m,4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.13 (d,J=6.6 Hz, 3H), 1.26 (m, 1H), 2.10-2.34 (m, 3H), 2.51-2.25 (m, 2H),3.00-3.45 (m, 6H), 3.45-3.67 (m, 3H), 3.67-3.39 (m, 2H), 4.30-4.43 (m,2H), 7.00-7.07 (m, 2H), 7.12-7.20 (m, 2H), 7.36-7.44 (m, 1H), 7.44-7.51(m, 4H).

ESI-Mass; 424 (MH+).

Example 5 Synthesis of1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-fluorophenoxy)propyl]piperazine

The title compound (95 mg, 64%) was obtained as a colorless oil from2-(1-methylethyl)-4-oxo-2-phenyl butyronitrile (70 mg) and1-[3-(4-fluorophenoxy)propyl]piperazine (83 mg) in the same manner as inExample 1. This free compound (94 mg) was treated in the same manner asin Example 1 to give the hydrochloride (97 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.20 (d, J=6.6Hz, 3H), 1.88-2.16 (m, 5H), 2.30-2.57 (m, 12H), 3.92-4.00 (m, 2H),6.78-6.85 (m, 2H), 6.92-6.98 (m, 2H), 7.28-7.34 (m, 1H), 7.36-7.40 (m,4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.13 (d,J=6.6 Hz, 3H), 2.10-2.28 (m, 4H), 2.57-2.70 (m, 2H), 3.00-3.90 (m, 11H),4.00-4.10 (m, 2H), 6.93-7.00 (m, 2H), 7.10-7.17 (m, 2H), 7.37-7.44 (m,1H), 7.46-7.50 (m, 4H).

ESI-Mass; 424 (MH+).

Example 6 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine

The title compound (135 mg, 96%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (70 mg) and1-(4-phenoxypropyl)piperazine (76 mg) in the same manner as inExample 1. This free compound (135 mg) was treated in the same manner asin Example 1 to give the hydrochloride (140 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.6 Hz, 3H), 1.05-1.17 (m,2H), 1.20 (d, J=6.6 Hz, 3H), 1.24-1.28 (m, 1H), 1.50-1.58 (m, 1H),1.61-1.69 (m, 1H), 1.73-1.82 (m, 2H), 1.88 (dt, J=4.4 Hz, 12.4 Hz, 1H),2.05-2.18 (m, 2H), 2.20-2.50 (m, 11H), 3.96 (t, J=6.4 Hz, 2H), 6.88 (d,J=7.2 Hz, 2H), 6.92 (t, J=7.2 Hz, 1H), 7.23-7.40 (m, 3H), 7.44-7.49 (m,4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.33 (m, 1H), 1.55-1.95 (m, 4H), 2.00-2.30 (m, 3H),2.95-3.25 (m, 4H), 3.25-3.85 (m, 9H), 3.98 (t, J=6 Hz, 2H), 6.85-6.97(m, 3H), 7.28 (br-t, J=8 Hz, 2H), 7.34-7.40 (m, 1H), 7.40-7.48 (m, 4H).

ESI-Mass; 434 (MH+).

Example 7 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-phenoxyethyl)piperazine

The title compound (520 mg, 64%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (429 mg) and1-(2-phenoxyethyl)piperazine (644 mg) in the same manner as inExample 1. This free compound (510 mg) was treated in the same manner asin Example 1 to give the hydrochloride (600 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.02-1.16 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.88 (dt, J=4.4, 12.4Hz, 1H), 2.08-2.18 (m, 2H), 2.27 (br-t, J=7.6 Hz, 2H), 2.30-2.46 (m,4H), 2.46-2.70 (m, 4H), 2.78 (t, J=5.8 Hz, 2H), 4.08 (t, J=5.8 Hz, 2H),6.88-6.95 (m, 3H), 7.24-7.30 (m, 3H), 7.32-7.38 (m, 4H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.55-1.65 (m, 1H), 2.05-2.25 (m, 3H),2.90-3.65 (m, 12H), 4.20-4.40 (m, 2H), 6.69-6.99 (m, 3H), 7.29-7.33 (m,2H), 7.36-7.40 (m, 1H), 7.41-7.48 (m, 4H).

ESI-Mass; 406 (MH+).

Example 8 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine

The title compound (1.19 g, 71%) was obtained as a yellow oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (800 mg) and1-[2-(4-nitrophenoxy)ethyl]piperazine (1.40 g) in the same manner as inExample 1. This free compound (225 mg) was treated in the same manner asin Example 1 to give the hydrochloride (255 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.4 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.4 Hz, 3H), 1.45-1.60 (m, 1H), 1.88 (dt, J=5.0, 13.0Hz, 1H), 2.08-2.20 (m, 2H), 2.28 (br-t, J=7.5 Hz, 2H), 2.30-2.45 (m,4H), 2.50-2.62 (m, 4H), 2.82 (t, J=5.8 Hz, 2H), 4.17 (t, J=5.8 Hz, 2H),6.94-6.96 (m, 2H), 7.26-7.31 (m, 1H), 7.36-7.37 (m, 4H), 8.18-8.20 (m,2H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆): δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.20-1.33 (m, 1H), 1.56-1.70 (m, 1H), 2.05-2.25 (m, 3H),3.00-3.80 (m, 12H), 4.45-4.60 (m, 2H), 7.18-7.24 (m, 2H), 7.34-7.41 (m,1H), 7.43-7.49 (m, 4H), 8.22-8.28 (m, 2H).

ESI-Mass; 451 (MH+).

Example 9 Synthesis of1-[4-Cyano-5-methyl-4-(4-methylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (376 mg, 59%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-(4-methylphenyl)pentane nitrile (334 mg) and1-[2-(4-fluorophenoxy)ethyl]piperazine (360 mg) in the same manner as inExample 1. This free compound (42 mg) was treated in the same manner asin Example 1 to give the hydrochloride (49 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.17 (m,1H), 1.18 (d, J=6.8 Hz, 3H), 1.48-1.61 (m, 1H), 1.85 (dt, J=4.4, 12.5Hz, 1H), 2.03-2.16 (m, 2H), 2.27 (t, J=7.1 Hz, 2H), 2.30-2.45 (m, 4H),2.34 (s, 3H), 2.45-2.65 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8Hz, 2H), 6.81-6.85 (m, 2H), 6.92-6.98 (m, 2H), 7.15 (d, J=8.4 Hz, 2H),7.23 (d, J=8.4 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.60 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.6Hz, 3H), 1.18-1.32 (m, 1H), 1.52-1.65 (m, 1H), 1.86-1.96 (m, 1H),2.06-2.17 (m, 2H), 2.20 (s, 3H), 2.90-3.00 (m, 1H), 3.04-3.13 (m, 1H),3.22-3.48 (m, 10H), 4.18 (t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H), 6.92-6.99(m, 2H), 7.18 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H).

ESI-Mass; 438 (MH+).

Example 10 Synthesis of1-[4-Cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (599 mg, 63%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-(4-chlorophenyl)pentane nitrile (496 mg) and1-[2-(4-fluorophenoxy)ethyl]piperazine (490 mg) in the same manner as inExample 1. This free compound (46 mg) was treated in the same manner asin Example 1 to give the hydrochloride (53 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.13-1.16 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.48-1.61 (m, 1H), 1.84 (dt, J=4.4, 12.5Hz, 1H), 2.03-2.19 (m, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.30-2.46 (m, 4H),2.46-2.64 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H),6.81-6.85 (m, 2H), 6.93-6.98 (m, 2H), 7.30 (d, J=8.6 Hz, 2H), 7.34 (d,J=8.6 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.60 (d, J=6.6 Hz, 3H), 1.02 (d, J=6.6Hz, 3H), 1.18-1.30 (m, 1H), 1.54-1.67 (m, 1H), 1.87-1.96 (m, 1H),2.06-2.20 (m, 2H), 2.95-3.05 (m, 1H), 3.08-3.17 (m, 1H), 3.32-3.58 (m,10H), 4.20 (t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H), 6.93-6.98 (m, 2H), 7.30(d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H).

ESI-Mass; 458 (MH+).

Example 11 Synthesis of1-[4-Cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (404 mg, 62%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-(4-methoxyphenyl)pentane nitrile (345 mg) and1-[2-(4-fluorophenoxy)ethyl]piperazine (350 mg) in the same manner as inExample 1. This free compound (59 mg) was treated in the same manner asin Example 1 to give the hydrochloride (68 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.07-1.19 (m,1H), 1.18 (d, J=6.8 Hz, 3H), 1.48-1.61 (m, 1H), 1.77-1.87 (m, 1H),2.03-2.15 (m, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.30-2.46 (m, 4H), 2.46-2.65(m, 4H), 2.77 (t, J=5.8 Hz, 2H), 3.81 (s, 3H), 4.04 (t, J=5.8 Hz, 2H),6.81-6.85 (m, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.93-6.97 (m, 2H), 7.26 (d,J=9.0 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.60 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6Hz, 3H), 1.21-1.35 (m, 1H), 1.54-1.68 (m, 1H), 1.83-1.96 (m, 1H),2.02-2.19 (m, 2H), 2.97-3.09 (m, 1H), 3.12-3.21 (m, 1H), 3.35-3.67 (m,10H), 3.70 (s, 3H), 4.23 (br-t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H),6.90-6.99 (m, 3H), 7.27 (d, J=8.8 Hz, 2H).

ESI-Mass; 454 (MH+).

Example 12 Synthesis of1-[4-Cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (74 mg, 71%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-(4-carbomethoxyphenyl)pentane nitrile (59 mg)and 1-[2-(4-fluorophenoxy)ethyl]piperazine (53 mg) in the same manner asin Example 1. This free compound (10 mg) was treated in the same manneras in Example 1 to give the hydrochloride (11 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.76 (d, J=6.8 Hz, 3H), 1.10-1.13 (m,1H), 1.22 (d, J=6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.91 (dt, J=4.4, 12.5Hz, 1H), 2.09-2.24 (m, 2H), 2.27 (t, J=7.1 Hz, 2H), 2.27-2.46 (m, 4H),2.46-2.70 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 3.93 (s, 3H), 4.04 (t, J=5.8Hz, 2H), 6.81-6.85 (m, 2H), 6.93-6.98 (m, 2H), 7.46 (d, J=8.2 Hz, 2H),8.04 (d, J=8.2 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.60 (d, J=6.6 Hz, 3H), 1.05 (d, J=6.6Hz, 3H), 1.18-1.29 (m, 1H), 1.55-1.70 (m, 1H), 1.94-2.04 (m, 1H),2.12-2.25 (m, 2H), 2.99-3.10 (m, 1H), 3.11-3.22 (m, 1H), 3.35-3.68 (m,10H), 3.80 (s, 3H), 4.22 (br-t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H),6.93-6.99 (m, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H).

ESI-Mass; 482 (MH+).

Example 13 Synthesis of1-[4-Cyano-5-methyl-4-(4-hydroxymethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

Lithium borohydride (3 mg) was added to a tetrahydrofuran solution (2ml) containing the1-[4-cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine(64 mg) obtained in Example 12, and the mixture was heated under refluxfor 3 hours. The reaction mixture was cooled to room temperature, then 1N hydrochloric acid (1 ml) was added thereto, and the mixture wasstirred at room temperature for 10 minutes. The organic layer waspartitioned by adding aqueous saturated sodium bicarbonate and ethylacetate, washed with water, and dried over sodium sulfate anhydrous. Theresidue obtained by evaporation was purified by Cromatorex NH silica gelcolumn chromatography (hexane/ethyl acetate system) to give the titlecompound (57 mg, 95%) as a colorless oil. 4 N hydrogen chloride/ethylacetate solution was added at room temperature to a solution of thisfree compound (27 mg) in methanol. The solution was stirred for 10minutes, and then the solvent was evaporated, whereby the hydrochloride(31 mg) of the title compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.87 (dt, J=4.4, 12.5Hz, 1H), 2.07-2.20 (m, 2H), 2.27 (t, J=7.1 Hz, 2H), 2.29-2.44 (m, 4H),2.46-2.61 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H), 4.69(s, 2H), 4.70-4.72 (m, 1H), 6.79-6.85 (m, 2H), 6.92-6.98 (m, 2H),7.33-7.40 (br-s, 4H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.60 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6Hz, 3H), 1.17-1.31 (m, 1H), 1.53-1.68 (m, 1H), 1.89-1.99 (m, 1H),2.09-2.20 (m, 2H), 2.93-3.02 (m, 1H), 3.06-3.15 (m, 1H), 3.24-3.54 (m,10H), 4.19 (t, J=4.9 Hz, 2H), 4.51 (s, 2H), 6.82-6.87 (m, 2H), 6.93-6.99(m, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H).

ESI-Mass; 454 (MH+).

Example 14 Synthesis of1-[4-Cyano-5-methyl-4-(4-hydroxyiminomethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

DMSO (0.5 ml), triethylamine (0.5 ml) and sulfur trioxide pyridine (31mg) was added to the1-[4-cyano-5-methyl-4-(4-hydroxymethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazineobtained in Example 13, and the mixture was stirred at room temperaturefor 30 minutes. Brine and ether were added to the reaction mixture, andthe organic layer was partitioned, dried over sodium sulfate anhydrous,and evaporated. The resulting residue was dissolved in ethanol (2 ml),then hydroxylamine hydrochloride (7 mg) and sodium acetate (9 mg) wereadded thereto, and the mixture was stirred at room temperature for 12hours. Aqueous saturated sodium bicarbonate and ethyl acetate were addedto the reaction mixture, and the organic layer was partitioned, washedwith water, dried over sodium sulfate anhydrous, and evaporated. Theresulting residue was purified by silica gel column chromatography(toluene/acetone system) to give the title compound (23 mg, 74%) as acolorless oil. 4 N hydrogen chloride/ethyl acetate solution was added atroom temperature to a solution of this free compound (8 mg) in methanol.The reaction mixture was stirred for 10 minutes, and then the solventwas evaporated, whereby the hydrochloride (9 mg) of the title compoundwas obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.8Hz, 3H), 1.20-1.31 (m, 1H), 1.55-1.70 (m, 1H), 1.92 (dt, J=4.4, 12.5 Hz,1H), 2.04-2.20 (m, 2H), 2.38-2.45 (m, 2H), 2.48-2.66 (m, 4H), 2.66-2.82(m, 4H), 2.85 (t, J=5.8 Hz, 2H), 4.08 (t, J=5.8 Hz, 2H), 6.79-6.84 (m,2H), 6.92-6.97 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),8.06 (s, 1H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.61 (d, J=6.6 Hz, 3H), 1.04 (d, J=6.6Hz, 3H), 1.17-1.31 (m, 1H), 1.53-1.68 (m, 1H), 1.90-2.00 (m, 1H),2.10-2.23 (m, 2H), 2.91-3.01 (m, 1H), 3.04-3.14 (m, 1H), 3.22-3.46 (m,10H), 4.18 (t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H), 6.92-6.99 (m, 2H), 7.40(d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 8.13 (s, 1H).

ESI-Mass; 467 (MH+).

Example 15 Synthesis of1-[4-Cyano-5-methyl-4-(4-cyanonphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

Carbonyl diimidazole (26 mg) was added to the solution of the1-[(4-cyano-5-methyl-4-(4-hydroxyiminomethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine(15 mg) obtained in Example 14 in tetrahydrofuran (2 ml), and thenstirred at 50° C. for 12 hours. Brine and ethyl acetate were added tothe reaction mixture, and the organic layer was partitioned, washed withwater, dried over sodium sulfate anhydrous, and evaporated. Theresulting residue was purified by silica gel column chromatography(toluene/acetone system) to give the title compound (9 mg, 63%) as acolorless oil. 4 N hydrogen chloride/ethyl acetate solution was added atroom temperature to a solution of this free compound (9 mg) in methanol.The reaction mixture was stirred for 10 minutes, and then the solventwas evaporated, whereby the hydrochloride (10 mg) of the title compoundwas obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 0.96-1.10 (m,1H), 1.22 (d, J=6.8 Hz, 3H), 1.49-1.63 (m, 1H), 1.89 (dt, J=4.4, 12.5Hz, 1H), 2.07-2.25 (m, 2H), 2.30 (t, J=7.0 Hz, 2H), 2.32-2.46 (m, 4H),2.46-2.65 (m, 4H), 2.78 (t, J=5.8 Hz, 2H), 4.05 (t, J=5.8 Hz, 2H),6.81-6.85 (m, 2H), 6.93-6.98 (m, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.69 (d,J=8.6 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.59 (d, J=6.6 Hz, 3H), 1.04 (d, J=6.6Hz, 3H), 1.11-1.26 (m, 1H), 1.54-1.69 (m, 1H), 1.93-2.03 (m, 1H),2.10-2.24 (m, 2H), 2.98-3.08 (m, 1H), 3.09-3.20 (m, 1H), 3.31-3.60 (m,10H), 4.21 (t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H), 6.92-6.99 (m, 2H), 7.51(d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H).

ESI-Mass; 449 (MH+).

Example 16 Synthesis of1-[4-Cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (356 mg, 90%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-(4-nitrophenyl)pentane nitrile (219 mg) and1-[2-(4-fluorophenoxy)ethyl]piperazine (210 mg) in the same manner as inExample 1. The free compound (44 mg) thereof was treated in the samemanner as in Example 1 to give the hydrochloride (50 mg) of the titlecompound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 0.96-1.10 (m,1H), 1.24 (d, J=6.8 Hz, 3H), 1.50-1.63 (m, 1H), 1.92 (dt, J=4.4, 12.5Hz, 1H), 2.11-2.26 (m, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.30-2.44 (m, 4H),2.46-2.66 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H),6.80-6.85 (m, 2H), 6.93-6.98 (m, 2H), 7.58 (d, J=9.0 Hz, 2H), 8.25 (d,J=9.0 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.61 (d, J=6.6 Hz, 3H), 1.05 (d, J=6.6Hz, 3H), 1.15-1.30 (m, 1H), 1.57-1.72 (m, 1H), 1.96-2.06 (m, 1H),2.17-2.28 (m, 2H), 3.03-3.12 (m, 1H), 3.13-3.24 (m, 1H), 3.35-3.65 (m,10H), 4.22 (br-t, J=4.9 Hz, 2H), 6.82-6.87 (m, 2H), 6.92-6.99 (m, 2H),7.58 (d, J=8.8 Hz, 2H), 8.18 (d, J=8.8 Hz, 2H).

ESI-Mass; 469 (MH+).

Example 17 Synthesis of1-[4-Cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

10% palladium/carbon (10 mg) was added to an ethyl acetate solution (5ml) containing the1-[(4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine(312 mg) obtained in Example 16, and then stirred for 5 hours at roomtemperature under a hydrogen gas stream. The reaction mixture wasfiltered, and the filtrate was evaporated. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) whereby the title compound (87 mg, 30%) was obtained as acolorless oil. A 4 N hydrogen chloride/ethyl acetate solution was addedto a solution of this free compound (26 mg) in methanol. After thereaction mixture was stirred for 10 minutes, the solvent was evaporated,whereby the hydrochloride (32 mg) of the title compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.16 (d, J=6.8Hz, 3H), 1.47-1.61 (m, 1H), 1.77-1.85 (m, 2H), 1.99-2.14 (m, 2H), 2.28(t, J=7.1 Hz, 2H), 2.30-2.45 (m, 4H), 2.46-2.67 (m, 4H), 2.77 (t, J=5.8Hz, 2H), 3.68 (br-s, 2H), 4.04 (t, J=5.8 Hz, 2H), 6.66 (d, J=8.4 Hz,2H), 6.81-6.85 (m, 2H), 6.92-6.98 (m, 2H), 7.11 (d, J=8.4 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.59 (d, J=6.6 Hz, 3H), 1.02 (d, J=6.6Hz, 3H), 1.19-1.31 (m, 1H), 1.56-1.69 (m, 1H), 1.93-2.04 (m, 1H),2.09-2.23 (m, 2H), 3.04-3.14 (m, 1H), 3.15-3.24 (m, 1H), 3.39-3.72 (m,10H), 4.24 (br-t, J=4.9 Hz, 2H), 6.83-6.87 (m, 2H), 6.93-6.99 (m, 2H),7.35 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H).

ESI-Mass; 439 (MH+).

Example 18 Synthesis of1-[4-Cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

Acetic acid anhydride (1 ml) was added to a pyridine solution (2 ml)containing the1-[4-cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine(15 mg) obtained in Example 17, and then stirred at room temperature for12 hours. The reaction mixture was evaporated, and the residue waspurified by silica gel column chromatography (toluene/acetone system),whereby the title compound (15 mg, 91%) was obtained as a colorless oil.A 4 N hydrogen chloride/ethyl acetate solution was added to a solutionof the free compound (15 mg) thereof in methanol. After the reactionmixture was stirred for 10 minutes, the solvent was evaporated, wherebythe hydrochloride (17 mg) of the title compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.10-1.22 (m,1H), 1.18 (d, J=6.8 Hz, 3H), 1.49-1.63 (m, 1H), 1.87 (dt, J=4.0, 12.8Hz, 1H), 2.03-2.17 (m, 2H), 2.19 (s, 3H), 2.35 (t, J=7.1 Hz, 2H),2.38-2.54 (m, 4H), 2.55-2.75 (m, 4H), 2.81 (t, J=5.8 Hz, 2H), 4.06 (t,J=5.8 Hz, 2H), 6.79-6.85 (m, 2H), 6.93-6.99 (m, 2H), 7.29 (br-s, 1H),7.31 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.61 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6Hz, 3H), 1.20-1.35 (m, 1H), 1.54-1.69 (m, 1H), 1.86-1.99 (m, 1H), 2.03(s, 3H), 2.05-2.22 (m, 2H), 2.96-3.06 (m, 1H), 3.08-3.20 (m, 1H),3.33-3.59 (m, 10H), 4.21 (br-t, J=4.9 Hz, 2H), 6.83-6.88 (m, 2H),6.94-7.00 (m, 2H), 7.33 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).

ESI-Mass; 481 (MH+).

Example 19 Synthesis of1-[4-Cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

p-Formaldehyde (30 mg) and sodium cyano borohydride (30 mg) were addedto an acetic acid (2 ml) solution containing the1-[4-cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine(21 mg) obtained in Example 17, and then stirred at room temperature for12 hours. The reaction mixture was evaporated, and the organic layer waspartitioned by adding aqueous saturated sodium bicarbonate and ethylacetate. The organic layer was washed with water, dried over sodiumsulfate anhydrous, and evaporated. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (12 mg, 56%) was obtained as acolorless oil. A 4 N hydrogen chloride/ethyl acetate solution was addedto a solution of this free compound (12 mg) in methanol. After thereaction mixture was stirred for 10 minutes, the solvent was evaporated,whereby the hydrochloride (14 mg) of the title compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.8 Hz, 3H), 1.16 (d, J=6.8Hz, 3H), 1.17-1.24 (m, 1H), 1.49-1.62 (m, 1H), 1.82 (dt, J=4.0, 12.8 Hz,1H), 1.99-2.14 (m, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.30-2.47 (m, 4H),2.47-2.65 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 2.95 (s, 6H), 4.04 (t, J=5.8Hz, 2H), 6.68 (d, J=9.0 Hz, 2H), 6.80-6.85 (m, 2H), 6.92-6.98 (m, 2H),7.19 (d, J=9.0 Hz, 2H).

Hydrochloride;

¹H-NMR (400 MHz, D₂O); δ (ppm) 0.59 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6Hz, 3H), 1.17-1.30 (m, 1H), 1.55-1.70 (m, 1H), 1.94-2.05 (m, 1H),2.10-2.25 (m, 2H), 3.01-3.22 (m, 2H), 3.17 (s, 3H), 3.34-3.60 (m, 10H),4.22 (br-t, J=4.9 Hz, 2H), 6.83-6.88 (m, 2H), 6.94-6.99 (m, 2H), 7.55(br-s, 4H).

ESI-Mass; 467 (MH+).

Example 20 Synthesis of1-{[4-Cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (293 mg, 50%) was obtained as a yellow oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(2-thienyl)pentane nitrile (300 mg)synthesized from 2-thiophene acetonitrile, and1-[2-(4-fluorophenoxy)ethyl]piperazine (305 mg). This free compound (293mg) was treated in the same manner as in Example 1 to give thehydrochloride (220 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.90 (d, J=6.8 Hz, 3H), 1.18 (d, J=6.8Hz, 3H), 1.23-1.38 (m, 1H), 1.57-1.70 (m, 1H), 1.77 (dt, J=4.0 Hz, 12.0Hz, 2H), 2.00-2.10 (m, 1H), 2.11-2.20 (m, 1H), 2.26-2.35 (m, 2H),2.35-2.49 (m, 4H), 2.49-2.66 (m, 4H), 2.78 (t, J=5.8 Hz, 2H), 4.04 (t,J=5.8 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-6.99 (m, 3H), 7.11 (dd, J=1.2 Hz,3.6 Hz, 1H), 7.24-7.27 (m, 1H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.80 (d, J=6.8 Hz, 3H), 1.07 (d,J=6.8 Hz, 3H), 1.40-1.55 (m, 1H), 1.66-1.82 (m, 1H), 1.87-1.99 (m, 1H),2.06-2.30 (m, 2H), 3.00-4.0 (m, 12H), 4.34 (br-s, 2H), 6.98-7. 08 (m,3H), 7.10-7.18 (m, 3H), 7.57 (dd, J=1.2 Hz, 4.8 Hz, 1H).

ESI-Mass; 430 (MH+).

Example 21 Synthesis of1-{[4-Cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (325 mg, 54%) was obtained as a colorless oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(3-pyridyl)pentane nitrile (300 mg)synthesized from 3-pyridyl acetonitrile, and1-[2-(4-fluorophenoxy)ethyl]piperazine (311 mg). This free compound (325mg) was treated in the same manner as in Example 1 to give thehydrochloride (300 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.81 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.22 (d, J=6.8 Hz, 3H), 1.52-1.65 (m, 1H), 1.89-1.99 (m, 1H),2.10-2.24 (m, 2H), 2.25-2.32 (m, 2H), 2.32-2.46 (m, 4H), 2.46-2.64 (m,4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H), 6.80-6.86 (m, 2H),6.92-6.99 (m, 2H), 7.30-7.36 (m, 1H), 7.70-7.75 (m, 1H), 8.55-8.59 (m,1H), 8.63-8.67 (m, 1H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.69 (d, J=6.86 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.22-1.39 (m, 1H), 1.60-1.73 (m, 1H), 2.17-2.40 (m, 3H),2.95-3.85 (m, 12H), 4.31-4.42 (m, 2H), 6.97-7.06 (m, 2H), 7.09-7.18 (m,2H), 7.84-7.92 (m, 1H), 8.28-8.36 (m, 1H), 8.78-8.88 (m, 2H).

ESI-Mass; 425 (MH+).

Example 22 Synthesis of1-{[4-Cyano-5-methyl-4-(2-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (67 mg, 12%) was obtained as a colorless oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(2-fluorophenyl)pentane nitrile (290 mg)synthesized from 2-fluorophenyl acetonitrile, and1-[2-(4-fluorophenoxy)ethyl]piperazine (278 mg). This free compound (67mg) was treated in the same manner as in Example 1 to give thehydrochloride (60 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.80 (d, J=6.8 Hz, 3H), 1.04-1.18 (m,1H), 1.22 (d, J=6.8 Hz, 3H), 1.51-1.64 (m, 1H), 2.02-2.13 (m, 1H),2.15-2.66 (m, 12H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H),6.79-6.86 (m, 2H), 6.91-6.99 (m, 2H), 6.99-7.06 (m, 1H), 7.12-7.18 (m,1H), 7.26-7.34 (m, 1H), 7.55-7.62 (m, 1H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.73 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.20-1.39 (m, 1H), 1.57-1.73 (m, 1H), 2.08-2.20 (m, 2H),2.30-2.42 (m, 1H), 3.30-3.75 (m, 12H), 4.29 (br-s, 2H), 6.97-7.03 (m,2H), 7.10-7.17 (m, 2H), 7.24-7.32 (m, 2H), 7.42-7.53 (m, 2H).

ESI-Mass; 424 (MH+).

Example 23 Synthesis of1-[{4-Cyano-5-methyl-4-(3-flourophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (258 mg, 45%) was obtained as a colorless oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(3-fluorophenyl)pentane nitrile (300 mg)synthesized from 3-fluorophenyl acetonitrile and1-[2-(4-fluorophenoxy)ethyl]piperazine (289 mg). The free compound (258mg) thereof was treated in the same manner as in Example 1 to give thehydrochloride (80 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.8 Hz, 3H), 1.04-1.17 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.85 (dt, J=4.4 Hz, 13.6Hz, 1H), 2.03-2.20 (m, 2H), 2.22-2.31 (m, 2H), 2.31-2.46 (m, 4H),2.46-2.66 (m, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H),6.80-6.85 (m, 2H), 6.92-7.04 (m, 3H), 7.05-7.10 (m, 1H), 7.16-7.20 (m,1H), 7.30-7.37 (m, 1H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.8 Hz, 3H), 1.10 (d,J=6.8 Hz, 3H), 1.15-1.30 (m, 1H), 1.52-1.68 (m, 1H), 2.0-2.27 (m, 3H),3.30-3.75 (m, 12H), 4.28 (br-s, 2H), 6.96-7.03 (m, 2H), 7.10-7.17 (m,2H), 7.27-7.24 (m, 1H), 7.24-7.32 (m, 2H), 7.46-7.53 (m, 1H).

ESI-Mass; 424 (MH+).

Example 24 Synthesis of1-{[4-Cyano-5-methyl-4-(4-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (78 mg, 17%) was obtained as a colorless oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(4-fluorophenyl)pentane nitrile (242 mg)synthesized from 4-fluorophenyl acetonitrile and1-[2-(4-fluorophenoxy)ethyl]piperazine (233 mg). This free compound (78mg) was treated in the same manner as in Example 1 to give thehydrochloride (62 mg) of the title compound.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.771 (d, J=6.8 Hz, 3H), 1.02-1.18 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.48-1.62 (m, 1H), 1.80-1.89 (m, 1H),2.02-2.19 (m, 2H), 2.23-2.31 (m, 2H), 2.31-2.46 (m, 4H), 2.46-2.66 (m,4H), 2.77 (t, J=5.8 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H), 6.79-6.86 (m, 2H),6.93-6.99 (m, 2H), 7.02-7.09 (m, 2H), 7.31-7.37 (m, 2H).

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.8 Hz, 3H), 1.15-1.30 (m, 1H), 1.50-1.67 (m, 1H), 2.00-2.22 (m, 3H),2.95-3.80 (m, 12H), 4.30-(br-s, 2H), 6.97-7.03 (m, 2H), 7.10-7.17 (m,2H), 7.24-7.31 (m, 2H), 7.43-7.49 (m, 2H).

ESI-Mass; 424 (MH+).

Example 25 Synthesis of1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluourophenoxy)ethyl]piperazine

The free compound (0.17 g, 78%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-4-oxo-2-phenyl butyronitrile (0.12g) and 1-[2-(4-fluorophenoxy)ethyl]piperazine (0.12 g) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.8Hz, 3H), 1.95-2.16 (m, 3H), 2.32-2.48 (m, 6H), 2.48-2.62 (m, 4H), 2.77(t, J=6.0 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 6.79-6.85 (m, 2H), 6.92-6.98(m, 2H), 7.26-7.34 (m, 1H), 7.34-7.40 (m, 4H).

The above free compound (0.17 g) was treated in a usual manner to givethe hydrochloride (0.18 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 2.18-2.26 (m, 1H), 2.54-2.68 (m, 2H), 3.40-3.80 (m, 12H),4.32 (br-s, 2H), 6.96-7.03 (m, 2H), 7.10-7.18 (m, 2H), 7.34-7.42 (m,1H), 7.42-7.48 (m, 4H).

ESI-Mass; 410 (MH+).

Example 26 Synthesis of1-[(4-Cyano-4-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.35 g, 83%) of the title compound was obtained as acolorless oil from 2-methyl-5-oxo-2-phenyl pentane nitrile (0.22 g) and1-[2-(4-fluorophenoxy)ethyl]piperazine (0.24 g) in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.33-1.45 (m, 1H), 1.60-1.70 (m, 1H),1.72 (s, 3H), 1.91-2.00 (m, 2H), 2.30 (t, J=6.8 Hz, 3H), 2.41 (br-s,4H), 2.57 (br-s, 4H), 2.78 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H),6.80-6.86 (m, 2H), 6.92-6.99 (m, 2H), 7.27-7.33 (m, 1H), 7.35-7.45 (m,4H).

The above free compound (0.35 g) was treated in a usual manner to givethe hydrochloride (0.37 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 1.48-1.50 (m, 1H), 1.68 (s, 3H),1.72-1.86 (m, 1H), 1.95-2.05 (m, 2H), 3.04-3.18 (m, 1H), 3.20-3.80 (m,11H), 4.33 (br-s, 2H), 6.97-7.04 (m, 2H), 7.10-7.18 (m, 2H), 7.33-7.37(m, 1H), 7.40-7.51 (m, 4H).

ESI-Mass; 396 (MH+).

Example 27 Synthesis of1-[(4-Cyano-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.35 g, 83%) of the title compound was obtained as acolorless oil from 5-oxo-2-phenyl-2-propyl pentane nitrile (0.22 g) and1-[2-(4-fluorophenoxy)ethyl]piperazine (0.24 g) in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.87 (t, J=7.2 Hz, 3H), 1.06-1.20 (m,1H), 1.22-1.33 (m, 1H), 1.42-1.54 (m, 1H), 1.60-1.72 (m, 1H), 1.80-2.05(m, 4H), 2.28 (t, J=7.2 Hz, 2H), 2.39 (br-s, 4H), 2.56 (br-s, 4H), 2.77(t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-6.99(m, 2H), 7.26-7.32 (m, 1H), 7.34-7.40 (m, 4H).

The above free compound (0.35 g) was treated in a usual manner to givethe hydrochloride (0.37 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.82 (t, J=7.2 Hz, 3H), 0.92-1.05 (m,1H), 1.24-1.37 (m, 1H), 1.37-1.50 (m, 1H), 1.70-1.85 (m, 1H), 1.85-1.98(m, 2H), 1.98-2.10 (m, 2H), 3.00-3.18 (m, 2H), 3.20-3.80 (m, 10H), 4.33(br-s, 2H), 6.97-7.04 (m, 2H), 7.10-7.17 (m, 2H), 7.31-7.38 (m, 1H),7.39-7.47 (m, 4H).

ESI-Mass; 424 (MH+).

Example 28 Synthesis of1-[(4-Cyano-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.20 g, 83%) of the title compound was obtained as acolorless oil from 5-oxo-2-ethyl-2-phenyl pentane nitrile (0.13 g) and1-[2-(4-fluorophenoxy)ethyl]piperazine (0.13 g) in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.90 (t, J=7.2 Hz, 3H), 1.23-1.34 (m,1H), 1.59-1.71 (m, 1H), 1.88-2.09 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), 2.39(br-s, 4H), 2.56 (br-s, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz,2H), 6.80-6.86 (m, 2H), 6.92-6.99 (m, 2H), 7.27-7.33 (m, 1H), 7.34-7.40(m, 4H).

The above free base compound (0.20 g) was treated in a usual manner togive the hydrochloride (0.14 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.77 (t, J=7.2 Hz, 3H), 1.38-1.52 (m,1H), 1.70-1.84 (m, 1H), 1.90-2.10 (m, 4H), 3.00-3.24 (m, 2H), 3.24-3.80(m, 10H), 4.35 (br-s, 2H), 6.98-7.04 (m, 2H), 7.10-7.17 (m, 2H),7.32-7.38 (m, 1H), 7.39-7.47 (m, 4H).

ESI-Mass; 410 (MH+).

Example 29 Synthesis of1-[(4-Cyano-4-phenyl)octyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.22 g, 81%) of the title compound was obtained as acolorless oil from 2-butyl-5-oxo-2-phenyl pentane nitrile (0.16 g) and1-[2-(4-fluorophenoxy)ethyl]piperazine (0.14 g) in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.84 (t, J=7.2 Hz, 3H), 1.03-1.14 (m,1H), 1.20-1.36 (m, 3H), 1.37-1.50 (m, 1H), 1.58-1.62 (m, 1H), 1.83-2.06(m, 4H), 2.28 (t, J=7.2 Hz, 2H), 2.39 (br-s, 4H), 2.56 (br-s, 4H), 2.77(t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-6.99(m, 2H), 7.27-7.33 (m, 1H), 7.34-7.41 (m, 4H).

The above free compound (0.22 g) was treated in a usual manner to givethe hydrochloride (0.22 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆) (ppm) 0.78 (t, J=7.2 Hz, 3H), 0.88-1.00 (m,1H), 1.17-1.34 (m, 3H), 1.35-1.49 (m, 1H), 1.70-1.83 (m, 1H), 1.90-2.08(m, 4H), 2.98-3.20 (m, 2H), 3.20-3.80 (m, 10H), 4.32 (br-s, 2H),6.97-7.03 (m, 2H), 7.10-7.17 (m, 2H) 7.31-7.38 (m, 1H), 7.40-7.47 (m,4H).

ESI-Mass; 438 (MH+).

Example 30 Synthesis of1-[(4-Cyano-6-methyl-4-phenyl)hepthyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.23 g, 85%) of the title compound was obtained as acolorless oil from 2-(2-methylpropyl)-5-oxo-2-phenyl pentane nitrile(0.15 g) and 1-[2-(4-fluorophenoxy)ethyl]piperazine (0.14 g) in the samemanner as Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 0.87-0.94 (m,1H), 0.98 (d, J=6.4 Hz, 3H), 1.14-1.30 (m, 1H), 1.55-1.72 (m, 2H),1.84-2.05 (m, 3H), 2.26 (t, J=7.2 Hz, 2H), 2.38 (br-s, 4H), 2.77 (t,J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-6.99 (m,2H), 7.26-7.32 (m, 1H), 7.43-7.43 (m, 4H).

The above free compound (0.23 g) was treated in a usual manner to givethe hydrochloride (0.21 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.62 (d, J=6.4 Hz, 3H), 0.90 (d,J=6.4 Hz, 3H), 1.33-1.48 (m, 2H), 1.33-2.10 (m, 5H), 2.97-3.18 (m, 2H),3.20-3.80 (m, 10H), 4.38 (br-s, 2H), 6.97-7.04 (m, 2H), 7.10-7.17 (m,2H), 7.31-7.37 (m, 1H), 7.40-7.50 (m, 4H).

ESI-Mass; 438 (MH+).

Example 31 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-(fluorophenoxy)ethyl]piperazine

The free compound (100 mg, 26%) of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 2-fluorophenol (408 mg), triphenyl phosphine (263 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (480 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.61 (m, 1H), 1.89 (dt, J=4.4, 13.6Hz, 1H), 2.06-2.19 (m, 2H), 2.24-2.30 (m, 2H), 2.30-2.45 (m, 4H),2.45-2.66 (m, 4H), 2.82 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H),6.86-6.92 (m, 1H), 6.92-6.98 (m, 1H), 7.01-7.09 (m, 2H), 7.26-7.32 (m,1H), 7.33-7.38 (m, 4H).

The above free compound (100 mg) was treated in a usual manner to givethe hydrochloride (117 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.54-1.68 (m, 1H), 2.03-2.28 (m, 3H),2.90-3.70 (m, 12H), 4.30-4.44 (m, 2H), 6.95-7.03 (m, 1H), 7.12-7.27 (m,3H), 7.33-7.40 (m, 1H), 7.41-7.49 (m, 4H).

ESI-Mass; 424 (MH+).

Example 32 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

The free compound (204 mg, 53%) of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 3-fluorophenol (408 mg), triphenyl phosphine (263 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (480 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.61 (m, 1H), 1.88 (dt, J=4.4, 12.4Hz, 1H), 2.08-2.18 (m, 2H), 2.23-2.30 (m, 2H), 2.30-2.45 (m, 4H),2.45-2.65 (m, 4H), 2.78 (t, J=5.8 Hz, 2H), 4.06 (t, J=5.8 Hz, 2H),6.58-6.70 (m, 3H), 7.17-7.23 (m, 1H), 7.26-7.32 (m, 1H), 7.33-7.38 (m,4H).

The above free compound (204 mg) was treated in a usual manner to givethe hydrochloride (234 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 1.12 (d,J=6.4 Hz, 3H), 1.16-1.30 (m, 1H), 1.52-1.68 (m, 1H), 2.00-2.30 (m, 3H),3.00-3.70 (m, 12H), 4.20-4.40 (m, 2H), 6.78-6.90 (m, 3H), 7.30-7.39 (m,2H), 7.42-7.48 (m, 4H).

ESI-Mass; 424 (MH+).

Example 33 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-3-(4-fluorophenoxy)ethyl]piperazine33-1) 1-[5-(4-Fluorophenoxy)pentyl]piperazine

The free compound (1.94 g, 92%) of the title compound was obtained as acolorless oil from t-butyl-1-piperazine carboxylate (1.07 g) and4-fluorophenoxypentyl iodide (1.61 g) in the same manner as inPreparatory Example 4.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.50-1.90 (m, 10H), 2.34-2.50 (m, 4H),2.90-2.96 (m, 2H), 3.88-3.96 (m, 2H), 6.79-6.85 (m, 12H), 6.93-6.99 (m,2H).

33-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)pentyl]piperazine

The free compound (177 mg, 89%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (92mg) and 1-[3-(4-fluorophenyl)pentyl]piperazine (114 mg) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.40-1.90 (m, 10H), 2.05-2.20 (m, 2H),2.20-2.50 (m, 10H), 3.85-3.40 (m, 2H), 6.75-6.85 (m, 2H), 6.90-7.00 (m,2H), 7.25-7.40 (m, 5H).

The above free compound (175 mg) was treated in a usual manner to givethe hydrochloride (160 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.6 Hz, 3H), 1.09 (d,J=6.6 Hz, 3H), 1.20-1.35 (m, 1H), 1.40-1.60 (m, 2H), 1.60-1.80 (m, 6H),2.00-2.25 (m, 2H), 3.00-3.20 (m, 2H), 3.20-3.80 (m, 10H), 3.90-4.00 (m,2H), 6.86-6.96 (m, 2H), 7.00-7.11 (m, 2H), 7.30-7.46 (m, 5H).

ESI-Mass; 466 (MH+).

Example 34 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)ethyl]piperazine

The free compound (54 mg, 2.9%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl hexane nitrile (928mg) and 1-[3-(4-fluorophenyl)ethyl]piperazine (104 mg) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.4 Hz, 3H), 0.90-1.00 (m,1H), 1.19 (d, J=6.4 Hz, 3H), 1.32-1.42 (m, 1H), 1.45-1.52 (m, 1H),1.80-1.90 (m, 1H), 2.05-2.20 (m, 2H), 2.20-2.27 (m, 2H), 2.30-2.50 (m,4H), 2.50-2.65 (m, 4H), 2.78 (t, J=6.0 Hz, 2H), 4.05 (t, J=6.0 Hz, 2H),6.80-6.85 (m, 2H), 6.90-7.00 (m, 2H), 7.28-7.32 (m, 1H), 7.32-7.40 (m,4H).

This free compound (54 mg) was treated in a usual manner to give thehydrochloride (40 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.4 Hz, 3H), 0.83 (m, 1H),1.13 (d, J=6.4, 3H), 1.15-1.30 (m, 1H), 1.55-1.75 (m, 1H), 2.00-2.30 (m,3H), 2.95-3.10 (m, 1H), 3.30-3.80 (m, 4H), 4.34 (m, 2H), 6.95-7.05 (m,2H), 7.10-7.20 (m, 2H), 7.30-7.40 (m, 2H), 7.40-7.50 (m, 4H).

ESI-Mass; 438 (MH+).

Example 35 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-difluorophenoxy)ethyl]piperazine

The free compound (96 mg, 24%) of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 3,4-difluorophenol (360 mg), triphenyl phosphine (290 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (440 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.48-1.61 (m, 1H), 1.88 (dt, J=4.4, 13.6Hz, 1H), 2.08-2.18 (m, 2H), 2.27 (br-t, J=7.6 Hz, 2H), 2.30-2.46 (m,4H), 2.46-2.62 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 4.01 (t, J=5.8 Hz, 2H),6.55-6.60 (m, 1H), 6.68-6.74 (m, 1H), 7.00-7.07 (m, 1H), 7.26-7.31 (m,1H), 7.34-7.38 (m, 4H).

The above free compound (96 mg) was treated in a usual manner to givethe hydrochloride (110 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.17-1.33 (m, 1H), 1.54-1.70 (m, 1H), 2.05-2.25 (m, 3H),3.00-3.80 (m, 12H), 4.25-4.40 (m, 2H), 6.81-6.87 (m, 1H), 7.12-7.20 (m,1H), 7.34-7.42 (m, 2H), 7.42-7.49 (m, 4H).

ESI-Mass; 422 (MH+).

Example 36 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine36-1) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine

The free compound (1.06 g, 75%)of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile(1.00 g) and 1-piperazine ethanol (1.21 g) in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.63 (m, 1H), 1.88 (dt, J=4.4 Hz, 12.8Hz, 1H), 2.08-2.19 (m, 2H), 2.22-2.30 (m, 2H), 2.30-2.41 (m, 4H),2.41-2.55 (m, 4H), 2.52 (t, J=5.8 Hz, 2H), 3.57 (t, J=5.8 Hz, 2H),7.26-7.32 (m, 1H), 7.34-7.39 (m, 4H).

ESI-Mass 330 (MH+).

36-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (500mg), 4-chlorophenol (390 mg) and triphenyl phosphine (796 mg) weredissolved in tetrahydrofuran (15.0 ml), then a solution of 40%azodicarboxylic acid diethyl ester/toluene solution (529 mg) intetrahydrofuran (5 ml) was added thereto, and the mixture was stirred atroom temperature overnight. The reaction mixture was evaporated, and theresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system), whereby the free compound (47 mg, 7%) ofthe title compound was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.19 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.65 (m, 1H), 1.88 (dt, J=4.4, 12.8Hz, 1H), 2.08-2.18 (m, 2H), 2.27 (br-t, J=7.2 Hz, 2H), 2.30-2.43 (m,4H), 2.50-2.62 (m, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H),6.80-6.84 (m, 2H), 7.19-7.23 (m, 2H), 7.25-7.31 (m, 1H), 7.33-7.38 (m,4H).

The above free compound (47 mg) was treated in a usual manner to givethe hydrochloride (54 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.30-1.45 (m, 1H), 1.59-1.72 (m, 1H), 2.08-2.25 (m, 3H),3.00-4.35 (m, 12H), 4.38-4.49 (m, 2H), 7.07-7.34 (m, 2H), 7.34-7.40 (m,3H), 7.42-7.48 (m, 4H).

ESI-Mass; 440 (MH+).

Example 37 Synthesis of1-{[4-Cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound (390 mg, 68%) was obtained as a colorless oil in thesame manner as in Example 1 from2-(1-methylethyl)-5-oxo-2-(3,4-dichlorophenyl)pentane nitrile (330 mg)synthesized from 3,4-dichlorophenyl acetonitrile, and1-[2-(4-fluorophenoxy)ethyl]piperazine (312 mg).

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.8 Hz, 3H), 1.02-1.15 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.65 (m, 1H), 1.78-89 (m, 1H),2.02-2.20 (m, 2H), 2.22-2.48 (m, 6H), 2.48-2.66 (m, 4H), 2.78 (t, J=5.8Hz, 2H), 4.04 (t, J=5.8 Hz, 2H), 6.80-6.86 (m, 2H), 6.92-6.99 (m, 2H),7.23 (dd, J=2 Hz, 8.4 Hz, 1H), 7.43-7.48 (m, 2H).

The above free compound (390 mg) was treated in a usual manner to givethe hydrochloride (348 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.6 Hz, 3H), 1.10 (d,J=6.6 Hz, 3H), 1.16-1.30 (m, 1H), 1.531-1.68 (m, 1H), 2.02-2.30 (m, 3H),2.97-3.74 (m, 12H), 4.24-4.38 (br-s, 2H), 6.97-7.03 (m, 2H), 7.10-7.17(m, 2H), 7.41-7.46 (m, 1H), 7.66 (d, J=2.20 Hz, 1H), 7.72 (d, J=8.42 Hz,1H).

ESI-Mass; 492 (MH+).

Example 38 Synthesis of1-[(4-Cyano-4-cyclohexyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The free compound (0.17 g, 67%) of the title compound was obtained as acolorless oil from 2-cyclohexyl-5-oxo-2-phenyl pentane nitrile (0.16 g)and 1-[2-(4-fluorophenoxy)ethyl]piperazine (0.12 g) in the same manneras in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.99-1.18 (m, 4H), 1.18-1.34 (m, 3H),1.48-1.77 (m, 4H), 1.82-1.92 (m, 2H), 2.05-2.23 (m, 2H), 2.27 (t, J=6.8Hz, 2H), 2.36 (br-s, 4H), 2.55 (br-s, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.04(t, J=6.0 Hz, 2H), 6.79-6.86 (m, 2H), 6.92-6.99 (m, 2H), 7.26-7.32 (m,1H), 7.33-7.39 (m, 4H).

The above free compound (0.17 g) was treated in a usual manner to givethe hydrochloride (0.19 g) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.80-0.92 (m, 1H), 0.96-1.34 (m, 6H),1.52-1.68 (m, 3H), 1.72-1.87 (m, 2H), 2.00-2.23 (m, 3H), 2.97-3.23 (m,2H), 3.24-3.80 (m, 10H), 4.34 (br-s, 2H), 6.97-7.04 (m, 2H), 7.10-7.17(m, 2H), 7.31-7.38 (m, 1H), 7.39-7.47 (m, 4H).

ESI-Mass; 464 (MH+).

Example 39 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine

The free compound (877 mg, 85%) of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (780mg), 4-methoxyphenol (1.18 g), triphenyl phosphine (680 mg) and 40%diazocarboxylic acid diethyl ester/toluene solution (1.24 g) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.65 (m, 1H), 1.88 (dt, J=4.4, 13.6Hz, 1H), 2.07-2.20 (m, 2H), 2.27 (br-t, J=7.2 Hz, 2H), 2.30-2.46 (m,4H), 2.46-2.65 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 4.03 (t,J=5.8 Hz, 2H), 6.79-6.86 (m, 4H), 7.26-7.32 (m, 1H), 7.34-7.40 (m, 4H).

The above free compound (877 mg) was treated in a usual manner to givethe hydrochloride (995 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.15-1.30 (m, 1H), 1.55-1.67 (m, 1H), 2.03-2.27 (m, 3H),2.96-3.85 (m, 12H), 3.70 (s, 3H), 4.16-4.33 (m, 2H), 6.85-6.96 (m, 4H),7.34-7.41 (m, 1H), 7.42-7.49 (m, 4H).

ESI-Mass; 436 (MH+).

Example 40 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine

The free compound (112 mg, 26%) of the title compound was obtained as acolorless oil from1-[(4-cyclo-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 2,3-dimethoxyphenol (720 mg), triphenyl phosphine (290 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (440 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.89 (dt, J=4.4, 13.6Hz, 1H), 2.08-2.18 (m, 2H), 2.24-2.30 (m, 2H), 2.30-2.44 (m, 4H),2.48-2.68 (m, 4H), 2.81 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H),4.10-4.15 (m, 2H), 6.56 (dd, J=1.2, 8.4 Hz, 1H), 6.57 (dd, J=1.2, 8.4Hz, 1H), 6.95 (dd, J=8.4, 8.4 Hz, 1H), 7.26-7.31 (m, 1H), 7.34-7.38 (m,4H).

The above free compound (112 mg) was treated in a usual manner to givethe hydrochloride (129 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.57-1.71 (m, 1H), 2.05-2.26 (m, 3H),3.00-3.90 (m, 12H), 3.68 (s, 3H), 3.78 (s, 3H), 4.26-4.42 (m, 2H),6.68-6.74 (m, 2H), 7.01 (t, J=8.4 Hz, 1H), 7.34-7.40 (m, 1H), 7.43-7.49(m, 4H).

ESI-Mass; 466 (MH+).

Example 41 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine

The free compound (104 mg, 25%) of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 3,4-dimethoxyphenol (720 mg), triphenyl phosphine (290 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (440 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.88 (dt, J=4.4, 13.6Hz, 1H), 2.08-2.19 (m, 2H), 2.28 (br-t, J=7.2 Hz, 2H), 2.30-2.46 (m,4H), 2.46-2.65 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 3.83 (s, 3H), 3.85 (s,3H), 4.03 (t, J=5.8 Hz, 2H), 6.38 (dd, J=2.8, 8.8 Hz, 1H), 6.53 (d,J=2.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.32-7.38 (m,4H).

The above free compound (104 mg) was treated in a usual manner to givethe hydrochloride (119 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.15-1.32 (m, 1H), 1.55-1.68 (m, 1H), 2.03-2.27 (m, 3H),3.00-3.85 (m, 12H), 3.69 (s, 3H), 3.74 (s, 3H), 4.20-4.35 (m, 2H), 6.48(br-dd, J=2.8, 8.8 Hz, 1H), 6.63 (br-d, J=2.8 Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 7.34-7.40 (m, 1H), 7.42-7.50 (m, 4H).

ESI-Mass; 466 (MH+).

Example 42 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine

In a hydrogen atmosphere,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine(925 mg) was dissolved in methanol (20 ml), then 10% Pd-C (90 mg) wasadded thereto, and the mixture was stirred overnight at roomtemperature. After 10% Pd-C was removed by filtration, the filtrate wasevaporated, whereby the free compound (840 mg, 97%) of the titlecompound was obtained as a yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.88 (dt, J=4.4, 12.8Hz, 1H), 2.08-2.18 (m, 2H), 2.27 (br-t, J=7.2 Hz, 2H), 2.30-2.45 (m,4H), 2.45-2.65 (m, 4H), 2.74 (t, J=6.0 Hz, 2H), 3.42 (br-s, 2H), 4.01(t, J=6.0 Hz, 2H), 6.61-6.65 (m, 2H), 6.71-6.76 (m, 2H), 7.25-7.32 (m,1H), 7.33-7.39 (m, 4H).

This free compound (272 mg) was treated in the same manner as in Example1 to give the hydrochloride (332 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.15-1.32 (m, 1H), 1.55-1.70 (m, 1H), 2.06-2.25 (m, 3H),2.97-3.75 (m, 14H), 4.30-4.42 (m, 2H), 7.07-7.13 (m, 2H), 7.32-7.40 (m,3H), 7.43-7.48 (m, 4H).

ESI-Mass; 421 (MH+).

Example 43 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminophenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine(243 mg) was dissolved in acetonitrile (5.0 ml) and 37% aqueousformaldehyde (1.0 ml), and sodium cyano borohydride (153 mg) and glacialacetic acid (0.2 ml) were added thereto, and the mixture was stirredovernight at room temperature. The organic layer was partitioned byadding aqueous saturated sodium bicarbonate and ethyl acetate, washedwith water, and dried over sodium sulfate anhydrous, and after thedrying agent was removed by filtration, the filtrate was evaporated, andthe residue was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system) to give the free compound(210 mg, 81%) of the title compound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.03-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.65 (m, 1H), 1.88 (dt, J=4.4, 12.4Hz, 1H), 2.06-2.19 (m, 2H), 2.19-2.30 (m, 2H), 2.30-2.45 (m, 4H),2.45-2.65 (m, 4H), 2.75 (t, J=5.8 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H),6.70-6.75 (m, 2H), 6.80-6.85 (m, 2H), 7.25-7.31 (m, 1H), 7.32-7.38 (m,4H).

The above free compound (210 mg) was treated in a usual manner to givethe hydrochloride (260 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.18-1.35 (m, 1H), 1.55-1.72 (m, 1H), 2.02-2.26 (m, 3H),3.07 (s, 6H), 3.00-3.90 (m, 12H), 4.30-4.50 (m, 2H), 7.10-7.20 (m, 2H),7.32-7.48 (m, 5H), 7.62-7.84 (m, 2H).

ESI-Mass; 449 (MH+).

Example 44 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-actamidophenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine(261 mg) was dissolved in acetic acid anhydride (2 ml) and pyridine (2ml), and the mixture was stirred overnight at room temperature. Theorganic layer was partitionedby adding water and ethyl acetate,washedwith water, and dried over sodium sulfate anhydrous, and after thedrying agent was removed by filtration, the filtrate was evaporated. Theresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system) to give the free compound (2 mg, 1%) ofthe title compound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.19 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (dt, J=4.4, 12.4Hz, 1H), 2.07-2.21 (m, 2H), 2.15 (s, 3H), 2.28 (br-t, J=7.2 Hz, 2H),2.30-2.46 (m, 4H), 2.46-2.65 (m, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.06 (t,J=6.0 Hz, 2H), 6.82-6.88 (m, 2H), 7.09 (br-s, 1H), 7.25-7.32 (m, 1H),7.32-7.41 (m, 6H).

The above free compound (2 mg) was treated in a usual manner to give thehydrochloride (2 mg) of the title compound as an amorphous.

Hydrochloride;

¹H-NMR (400 MHz, CD₃OD); δ (ppm) 0.74 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.8Hz, 3H), 1.30-1.50 (m, 1H), 1.70-1.90 (m, 1H), 2.05-2.35 (m, 3H), 2.08(s, 3H), 3.10-4.15 (m, 12H), 4.30-4.50 (m, 2H), 6.97 (br-d, J=8.8 Hz,2H), 7.30-7.38 (m, 1H), 7.39-7.50 (m, 7H).

ESI-Mass; 463 (MH+).

Example 45 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophenoxy)ethyl]piperazine

The free compound (122 mg, 30% of the title compound was obtained as acolorless oil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300mg), 4-methylthiophenol (430 mg), triphenyl phosphine (290 mg) and 40%azodicarboxylic acid diethyl ester/toluene solution (440 mg) in the samemanner as in Example 36-2.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.88 (dt, J=4.4, 13.2Hz, 1H), 2.08-2.18 (m, 2H), 2.24-2.30 (m, 2H), 2.30-2.43 (m, 4H), 2.44(s, 3H), 2.46-2.65 (m, 4H), 2.77 (t, J=5.8 Hz, 2H), 4.06 (t, J=5.8 Hz,2H), 6.82-6.86 (m, 2H), 7.23-7.31 (m, 3H), 7.33-7.39 (m, 4H).

The above free compound (122 mg) was treated in a usual manner to givethe hydrochloride (141 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.54-1.67 (m, 1H), 2.03-2.26 (m, 3H),2.42 (s, 3H), 2.95-3.80 (m, 12H), 4.20-4.36 (m, 2H), 6.93-6.99 (m, 2H),7.23-7.28 (m, 2H), 7.34-7.40 (m, 1H), 7.41-7.48 (m, 4H).

ESI-Mass; 452 (MH+).

Example 46 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanophenoxy)ethyl]piperazine46-1) 2-(2-Cyanophenoxy)ethylpiperazine

1-Formyl-4-(2-hydroxyethyl)piperazine (4.95 g) was dissolved intetrahydrofuran (100 ml), then triphenyl phosphine (10.14 g) and2-cyanophenol (3.57 g) were added thereto, and 40% azodicarboxylic aciddiethyl ester/toluene solution (13.5 ml) was added dropwise thereto, andthe title compound (1.60 g) was obtained in the same manner as inExample 47-1).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.48-2.67 (m, 4H), 2.86-2.97 (m, 6H),4.22 (t, J=5.8 Hz, 2H), 6.94-7.04 (m, 2H), 7.49-7.57 (m, 2H).

46-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanophenoxy)ethyl]piperazine

2-(1-Methylethyl)-5-oxo-2-phenyl pentane nitrile (150 mg),1-[2-(4-cyanophenoxy)ethyl]piperazine (200 mg), and acetic acid (0.10ml) were dissolved in dichloromethane (15 ml), then sodium triacetoxyborohydride (200 mg) was added thereto, and the mixture was stirredovernight at room temperature. The reaction mixture was poured intoaqueous saturated sodium bicarbonate, extracted with dichloromethane,washed with water and brine, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the free compound of the title compound as anoil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.8Hz, 3H), 1.25-1.27 (m, 1H), 1.90-2.26 (m, 4H), 2.26-3.01 (m, 12H),4.20-4.30 (m, 2H), 6.93-7.05 (m, 2H), 7.25-7.34 (m, 1H), 7.36-7.40 (m,4H), 7.49-7.58 (m, 2H).

The above free compound was dissolved in methanol, and 4 N hydrogenchloride/ethyl acetate solution was added thereto. The solvent andexcess hydrogen chloride were evaporated, and the product wasrecrystallized from methanol/ether to give the hydrochloride (168 mg) ofthe title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.16-1.32 (m, 1H), 1.57-1.60 (m, 1H), 2.06-2.30 (m, 3H),3.00-3.70 (m, 14H), 4.51 (brs, 2H), 7.12-7.18 (m, 1H), 7.27-7.31 (m,1H), 7.33-7.40 (m, 1H), 7.43-7.48 (m, 4H), 7.67-7.73 (m, 1H), 7.75-7.79(m, 1H).

ESI-Mass; 431 (MH+).

Example 47 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperazine47-1) 2-(4-Cyanophenoxy)ethylpiperazine

1-Formyl-4-(2-hydroxyethyl)piperazine (1.65 g) synthesized according toTetrahedron Letters, 26 (31), 3703-3706, was dissolved intetrahydrofuran (30 ml), then triphenyl phosphine (3.38 g) and4-cyanophenol (1.19 g) wereadded thereto, and 40% azodicarboxylic aciddiethyl ester/toluene solution (4.5 ml) was added dropwise thereto atroom temperature. After stirred for 4 hours, the reaction mixture waspoured into water and extracted with ethyl acetate and then with dilutedhydrochloric acid successively. The extract was basified with 2 N sodiumhydroxide, then extracted with ethyl acetate, washed with water, dried,and evaporated. It was dissolved in methanol, and 4 N hydrogenchloride/ethyl acetate was added thereto, and the mixture was leftovernight at room temperature. Ether was added to the reaction mixture,and the resulting crystals were filtered off to give the hydrochloride(1.72 g) of the title compound. This product was dissolved in methanol,then basified with aqueous sodium hydroxide, extracted with ethylacetate, washed with water, dried, and evaporated to give the titlecompound (0.92 g).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.45-2.60 (m, 4H), 2.81 (t, J=5.8 Hz,2H), 2.91 (t, J=5.8 Hz, 4H), 4.17 (t, J=5.8 Hz, 2H), 6.96 (d, J=7.7 Hz,2H), 7.59 (d, J=7.7 Hz, 2H).

47-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperazine

2-(1-Methylethyl)-5-oxo-2-phenyl pentane nitrile (150 mg),1-[2-(4-cyanophenoxy)ethyl]piperazine (200 mg), and acetic acid (0.10ml) were dissolved in dichloromethane (15 ml), then sodium triacetoxyborohydride (200 mg) was added thereto, and the mixture was stirredovernight at room temperature. The reaction mixture was poured intoaqueous saturated sodium bicarbonate, extracted with dichloromethane,washed with water and brine, and dried. After evaporating, the residuewas purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system) to give the free compound of the titlecompound as an oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.8Hz, 3H), 1.25-1.27 (m, 1H), 1.90-2.26 (m, 4H), 2.26-3.01 (m, 12H),4.08-4.23 (m, 2H), 6.91-6.96 (m, 2H), 7.27-7.34 (m, 1H), 7.35-7.40 (m,4H), 7.56-7.61 (m, 2H).

The above free compound was dissolved in methanol, and 4 N hydrogenchloride/ethyl acetate solution was added thereto. The solvent andexcess hydrogen chloride were evaporated to give the hydrochloride (134mg) of the title compound as an amorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.32 (m, 1H), 1.57-1.67 (m, 1H), 2.05-2.26 (m, 3H),2.98-3.82 (m, 14H), 4.45 (br-s, 2H), 7.14-7.19 (m, 2H), 7.34-7.40 (m,1H), 7.42-7.47 (m, 4H), 7.79-7.84 (m, 2H).

ESI-Mass; 431 (MH+).

Example 48 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (442mg) was dissolved in tetrahydrofuran (10 ml), then sodium hydride (54mg) was added thereto, and after the mixture was stirred for 15 minutesat room temperature, benzyl bromide (250 mg) was added thereto, and themixture was further stirred for 3 hours at room temperature. The organiclayer was partitioned by adding water and ethyl acetate, washed withwater, and dried over sodium sulfate anhydrous, and after the dryingagent was removed by filtration, the filtrate was evaporated, and theresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system) to give the free compound (270 mg, 48%) ofthe title compound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.88 (dt, J=4.4, 12.8Hz, 1H), 2.07-2.18 (m, 2H), 2.20-2.30 (m, 2H), 2.30-2.41 (m, 4H),2.41-2.55 (m, 4H), 2.59 (t, J=5.8 Hz, 2H), 3.56 (t, J=5.8 Hz, 2H), 4.52(s, 2H), 7.26-7.39 (m, 10H).

The above free compound (270 mg) was treated in a usual manner to givethe hydrochloride (315 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.15-1.30 (m, 1H), 1.55-1.68 (m, 1H), 2.00-2.37 (m, 3H),3.00-3.70 (m, 12H), 3.70-3.86 (m, 2H), 4.52 (s, 2H), 7.28-7.34 (m, 1H),7.34-7.39 (m, 5H), 7.42-7.48 (m, 4H).

ESI-Mass; 420 (MH+).

Example 49 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylthio)ethyl]piperazine49-1) 2-Chloroethyl 4-fluorophenyl Sulfide

According to J.O.C., 58, 4506, 1993, the title compound (10.9 g, 98%)was obtained as a yellow oil from 4-fluorothiophenol (7.4 g) and1,2-dichloroethane (58 ml).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 3.16 (t, J=8 Hz, 2H), 3.58 (t, J=8 Hz,2H), 7.03 (t, J=8.8 Hz, 2H), 7.41 (dd, J=5 Hz, 8.8 Hz, 2H).

49-2) 1-[2-(4-Fluorophenylthio)ethyl]piperazine andS-(4-fluorophenyl)thiocarbonate 1-(1-piperazinyl)ethyl

2-chloroethyl 4-fluorophenyl sulfide (2.556 g),N-(t-butoxycarbonyl)piperazine (2.686 g) and triethylamine (2 ml) weredissolved in tetrahydrofuran (30 ml) and stirred overnight at roomtemperature. The reaction mixture was diluted with ethyl acetate, washedwith water, dried, and evaporated. The residue was dissolved in ethanol(20 ml), then 5 N HCl (10 ml) was added thereto, and the mixture wasstirred at 50° C. for 1 hour. The reaction mixture was evaporated,basified with 5 N aqueous NaOH, and extracted with ethyl acetate, andthe organic layer was washed with water, dried, and evaporated. Theresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system) to give the title compounds (138 mg, 4%and 159 mg, 4%) respectively as colorless oil.

(1) 1-[2-(4-Fluorophenylthio)ethyl]piperazine

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.38-2.48 (br-s, 4H), 2.58 (t, J=7.6Hz, 2H), 2.88 (t, J=5 Hz, 4H), 3.00 (t, J=7.6 Hz, 2H), 6.99 (t, J=8.4Hz, 2H), 6.99 (dd, J=5.2 Hz, 8.4 Hz, 2H).

(2) S-(4-Fluorophenyl)thiocarbonate 1-(1-Piperazinyl)ethyl

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.72-2.88 (br-s, 4H), 3.11 (t, J=6.8Hz, 2H), 3.30-3.48 (m, 4H), 4.23 (t, J=6.8 Hz, 2H), 7.39-7.43 (m, 2H).

49-3)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylthio)ethyl]piperazine

The free compound (205 mg, 82%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (124mg) and 1-[2-(4-fluorophenylthio)ethyl]piperazine (138 mg) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.16 (m,1H), 1.19 (d, J=6.4 Hz, 3H), 1.48-1.60 (m, 1H), 1.87 (dt, J=4.4 Hz, 12.8Hz, 1H), 2.07-2.17 (m, 2H), 2.21-2.52 (m, 12H), 2.54-2.58 (m, 2H),2.95-2.99 (m, 2H), 6.98 (t, J=8.6 Hz, 2H), 7.26-7.38 (m, 7H).

The above free compound was treated in a usual manner to give thehydrochloride (181 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.8 Hz, 3H), 1.18-1.32 (m, 1H), 1.55-1.68 (m, 1H), 2.04-2.22 (m, 3H),2.95-3.75 (m, 14H), 7.19 (t, 8.8 Hz, 2H), 7.32-7.44 (m, 5H), 7.47 (dd,5.2 Hz, 8.8 Hz, 1H).

ESI-Mass; 440 (MH+).

Example 50 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylsulfonyl)ethyl]piperazine50-1) 1-[2-(4-Fluorophenylsulfonyl)ethyl]-4-[t-butoxycarbonyl)piperazine

2-Chloroethyl-4-fluorophenyl sulfone (2.5 g),N-(t-butoxycarbonyl)piperazine (2.3 g) and triethylamine (1.7 ml) weredissolved in tetrahydrofuran (30 ml) and stirred overnight at roomtemperature. The reaction mixture was diluted with ethyl acetate, washedwith water, dried, and evaporated. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (4.4 g, quantitatively) as acolorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.44 (s, 9H), 2.30 (t, J=5 Hz, 4H) 2.79(t, J=7.2 Hz, 2H), 3.26-3.31 (m, 6H), 7.22-7.27 (m, 2H), 7.92-7.96 (m,2H).

50-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylsulfonyl)ethyl]piperazine

1-[2-(4-Fluorophenylsulfonyl)ethyl]-4-(t-butoxycarbonyl)piperazine (4.4g) was dissolved in ethanol (20 ml), and 5 N HCl (10 ml) was addedthereto, and the mixture was stirred at 50° C. for 2 hours. The reactionmixture was evaporated, basified with 5 N aqueous NaOH, and extractedwith ethyl acetate. The organic layer was washed with water, dried, andevaporated. The free compound (80 mg, 46%) of the title compound wasobtained as a colorless oil from a part (101 mg) of the residue (2.567g) and 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (80 mg).

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.76 (d, J=6.8 Hz, 3/2H), 0.79 (d, 6.8Hz, 3/2H), 1.01-1.13 (m, 1H), 1.19 (d, J=6.8 Hz, 3/2H), 1.21 (d, 6.8 Hz,3/2H), 1.45-1.56 (m, 1H), 1.85 (ddd, J=4.4 Hz, 12 Hz, 13.6 Hz, 1/2H),1.98 (ddd, J=4.4 Hz, 12 Hz, 13.6 Hz, 1/2H), 2.06-2.38 (m, 12H), 2.74 (t,J=7.4 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H), 6.98 (t, J=8.6 Hz, 2H), 7.89-7.98(m, 2H).

The above free compound was treated in a usual manner to give thehydrochloride (35 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.64 (d, J=6.4 Hz, 3H), 0.91-1.33 (m,5H), 1.55-1.68 (m, 1H), 2.03-2.23 (m, 4H), 2.95-3.52 (m, 10H), 4.85-4.92(m, 2H), 7.29-7.45 (m, 5H), 7.52 (t, J=8.8 Hz, 2H), 7.98 (dd, 7.8 Hz,8.8 Hz, 2H).

ESI-Mass; 472 (MH+).

Example 51 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]-piperazine51-1) 1-[2-(4-Fluorophenylamino)ethyl]-4-benzylpiperazine

1-Benzyl-4-[N-(4-fluorophenyl)carbamoylmethyl] (12.05 g) was dissolvedin tetrahydrofuran (120 ml), then lithium aluminum hydride (1.39 g) wasadded thereto, and the mixture was heated under reflux. After thereaction mixture was cooled, water (1.4 ml), 5 N NaOH (1.4 ml) and water(4.2 ml) were added thereto in this order, and insolubles were filteredthrough Celite and evaporated. The residue was purified by Cromatorex NHsilica gel column chromatography (hexane/ethyl acetate system) to givethe title compound (10.2 g, 89%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.40-2.58 (br-s, 8H), 2.62 (t, J=6 Hz,2H), 3.52 (s, 2H), 4.15-4.24 (br-s, 1H), 6.56 (dd, J=4.4 Hz, 8.8 Hz,2H), 6.88 (t, J=8.8 Hz, 2H), 7.23-7.32 (m, 5H).

51-2) 1-[2-(4-Fluorophenylamino)ethyl]piperazine

The title compound (1.45 g, quantitative) was obtained as a colorlessoil from 1-[2-(4-fluorophenylamino)ethyl]-4-benzylpiperazine (2.05 g) inthe same manner as in Example 65-2).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.40-2.55 (br-s, 4H), 2.61 (t, J=5.8Hz, 2H), 2.90 (t, J=5 Hz, 4H), 3.11 (t, J=5.8 Hz, 2H), 4.13-4.30 (br-s,1H), 6.56 (dd, J=4.4 Hz, 8.8 Hz, 2H), 6.89 (t, J=8.8 Hz, 2H).

51-3)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]piperazine

The free compound (411 mg, 69%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (302mg) and 1-[2-(4-fluorophenylamino)ethyl]piperazine (313 mg) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.16 (m,1H), 1.20 (d, J=6.4 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.50 (m, 12H), 2.59 (t, J=5.8 Hz, 2H), 3.05-3.12(m, 2H), 4.10-4.20 (br-s, 1H), 6.53-6.57 (m, 2H), 6.85-6.91 (m, 2H),7.26-7.37 (m, 5H).

The above free compound (95 mg) was treated in a usual manner to givethe hydrochloride (73 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.4 Hz, 3H), 1.20-1.32 (m, 1H), 1.56-1.70 (m, 1H), 2.06-2.21 (m, 3H),3.05-3.75 (m, 14H), 6.73-6.80 (m, 2H), 6.99 (t, J=8.8 Hz, 2H), 7.31-7.43(m, 5H).

ESI-Mass; 423 (MH+).

Example 52 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylamino]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenylamino)ethyl]piperazine(121 mg) and p-formaldehyde (87 mg) were dissolved in acetic acid (5ml), then sodium triacetoxy borohydride (246 mg) was added thereto, andthe mixture was stirred overnight at room temperature. Saturated sodiumbicarbonate was added thereto, and the product was extracted with ethylacetate, washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the free compound (61 mg, 48%) of the titlecompound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.17 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.88 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.50 (m, 14H), 2.89 (s, 3H), 3.39 (t, J=7.6 Hz,2H), 6.61-6.64 (m, 2H), 6.88-6.94 (m, 2H), 7.27-7.37 (m, 5H).

The above free compound was treated in a usual manner to give thehydrochloride (57 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.63 (d, J=6.4 Hz, 3H), 1.09 (d,J=6.4 Hz, 3H), 1.21-1.31 (m, 1H), 1.58-1.68 (m, 1H), 2.06-2.22 (m, 3H),2.86 (s, 3H), 3.03-3.73 (m, 14H), 6.88 (dd, J=4.4 Hz, 8.8 Hz, 2H), 7.52(t, J=8.8 Hz, 2H), 7.32-7.43 (m, 5H).

ESI-Mass; 437 (MH+).

Example 53 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-acetylamino]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenylamino)ethyl]piperazine(97 mg) and triethylamine (0.06 ml) were dissolved in tetrahydrofuran (4ml), and acetyl chloride (0.03 ml) was added thereto under ice-cooling,and the mixture was stirred for 1 hour. Saturated sodium bicarbonate wasadded thereto, and the product was extracted with ethyl acetate, washedwith water, dried, and evaporated. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) to give the title compound (97 mg, 91%) as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.4 Hz, 3H), 1.06-1.14 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.48-1.59 (m, 1H), 1.80 (s, 3H), 1.88 (ddd,J=4.4 Hz, 12 Hz, 13.6 Hz, 1H), 2.07-2.48 (m, 14H), 3.78 (dt, J=2.4 Hz,6.8 Hz, 2H), 7.08 (t, J=8.8 Hz, 2H), 7.20 (dd, J=4.8 Hz, 8.8 Hz, 2H),7.27-7.36 (m, 5H).

The above free compound was treated in a usual manner to give thehydrochloride (62 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.4 Hz, 3H), 1.09 (d,J=6.4 Hz, 3H), 1.20-1.35 (m, 1H), 1.58-1.60 (m, 1H), 1.71 (s, 3H),2.05-2.21 (m, 3H), 3.00-4.00 (m, 14H), 7.28 (t, J=8.6 Hz, 2H), 7.32-7.43(m, 5H), 7.63 (dt, J=4.8 Hz, 8.6 Hz, 2H).

ESI-Mass; 465 (MH+).

Example 54 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methanesulfonylamino]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]piperazine(98 mg) and triethylamine (0.2 ml) were dissolved in tetrahydrofuran (4ml), and methane sulfonyl chloride (0.1 ml) was added thereto underice-cooling, and the mixture was stirred for 1 hour. Saturated sodiumbicarbonate was added thereto, and the product was extracted with ethylacetate, washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the free compound (103 mg, 91%) of the titlecompound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.16 (m,1H), 1.19 (d, J=6.4 Hz, 3H), 1.48-1.59 (m, 1H), 1.88 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.06-2.46 (m, 12H), 2.96 (s, 3H), 3.73 (t, J=6.8 Hz,2H), 7.08 (t, J=8.4 Hz, 2H), 7.27-7.36 (m, 7H).

The above free compound was treated in a usual manner to give thehydrochloride (63 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.4 Hz, 3H), 1.08 (d,J=6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.68 (m, 1H), 2.05-2.21 (m, 3H),3.05 (s, 3H), 3.10-3.70 (m, 12H), 4.03 (t, J=6.8 Hz, 2H), 7.27 (t, J=8.8Hz, 2H), 7.31-7.37 (m, 1H), 7.40-7.43 (m, 4H), 7.52 (dt, J=5 Hz, 8.8 Hz,2H).

ESI-Mass; 501 (MH+).

Example 55 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-benzylamino)ethyl]piperazine55-1) 1-(2-Aminoethyl)-4-(t-butoxycarbonyl)piperazine

N-(2-Aminoethyl)piperazine (24.4 g) and benzaldehyde (26.9 ml) weredissolved in toluene (250 ml), and a Dean-Stark device was attachedthereto, and the mixture was heated under reflux for 3 hours. Aftercooled to room temperature, a part (10 ml) of the reaction mixture wasremoved and concentrated to give N-[2-(benzylidene)aminoethyl]piperazine(1.4 g). Di (t-butyl) dicarbonate (45 g) was added to the remainder(about 240 ml) of the reaction mixture, and the mixture was stirredovernight at room temperature. 1 N aqueous potassium hydrogen sulfate(220 ml) was added thereto, and the mixture was vigorously stirred for 5hours at room temperature, and the aqueous layer was partitioned byadding diethyl ether. The aqueous layer was basified by adding sodiumhydroxide (solid), and the organic layer was partitioned by addingchloroform, washed with water, dried, and evaporated to give the titlecompound (14.9 g).

55-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

The previously obtained N-[2-(benzylidene)aminoethyl]piperazine (1.4 g),2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (808 mg) and aceticacid (0.9 ml) were dissolved in dichloroethane (10 ml) and sodiumtriacetoxy borohydride (2.5 g) was added thereto, and the title compound(311 mg, 20%) was obtained as a colorless oil in the same manner as inExample 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.17 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.88 (m, 3H), 2.05-2.19(m, 2H), 2.24-2.44 (m, 9H), 2.47 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz,2H), 3.78 (s, 2H), 7.22-7.37 (m, 10H).

The above free compound (300 mg) was treated in a usual manner to givethe hydrochloride (379 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.66 (m, 1H), 1.64 (m, 1H), 1.91-2.16 (m, 2H), 2.22 (t,J=6.8 Hz, 1H), 3.05-3.10 (m, 6H), 3.35-3.44 (m, 2H), 3.71 (br-s, 7H),4.16 (s, 2H), 7.34-7.40 (m, 2H), 7.42-7.44 (m, 6H), 7.56-7.59 (m, 2H),9.39 (br-s, 2H).

ESI-Mass; 419 (MH+).

Example 56 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(benzylamino)ethyl]piperazine(51 mg) and triethylamine (0.2 ml) were dissolved in tetrahydrofuran (5ml), and acetyl chloride (0.1 ml) was added thereto, and the mixture wasstirred overnight at room temperature. The organic layer was partitionedby adding water (5 ml) and ethyl acetate, washed with water, dried, andevaporated. The residue was purified by Cromatorex NH silica gel columnchromatography (ethyl acetate) to give the title compound (55 mg, 98%)as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.11 (m, 1H),1.19 (d, J=6.8 Hz, 3H), 1.54 (m, 1H), 1.81-1.96 (m, 2H), 2.11 (s, 3H),2.25 (m, 3H), 2.30 (m, 3H), 2.39 (m, 3H), 2.42 (t, J=7.2 Hz, 2H), 2.48(t, J=6.8 Hz, 2H), 3.30 (t, J=7.0 Hz, 1H), 3.46 (m, 1H), 4.60 (t, J=17.6Hz, 2H), 7.15-7.36 (m, 10H).

The above free compound (20 mg) was treated in a usual manner to givethe hydrochloride (23 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 0.86 (m, 1H),1.11 (d, J=6.4 Hz, 3H), 1.23 (m, 1H), 1.31 (d, J=6.0 Hz, 3H), 1.62 (m,1H), 2.11 (m, 1H), 2.22 (m, 1H), 2.67-3.44 (m, 12H), 4.35 (s, 2H), 7.37(m, 1H), 7.44 (m, 9H), 7.70 (m, 2H).

ESI-Mass; 462 (MH+).

Example 57 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(benzylamino)ethyl]piperazine(53 mg) and triethylamine (0.2 ml) were dissolved in tetrahydrofuran (5ml), and methane sulfonyl chloride (0.1 ml) was added thereto, and themixture was stirred overnight. The organic layer was partitioned byadding water (50 ml) and ethyl acetate, washed with water, dried, andevaporated. The residue was purified by Cromatorex NH silica gel columnchromatography (ethyl acetate) to give the title compound (61 mg, 97%)as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.12 (m, 1H),1.19 (d, J=6.6 Hz, 3H), 1.49-1.58 (m, 1H), 1.73 (m, 1H), 1.85-1.90 (m,1H), 2.07-2.30 (m, 8H), 2.29-2.40 (m, 5H), 2.98 (s, 3H), 3.28 (t, J=6.4Hz, 2H), 4.11 (s, 2H), 7.25-7.40 (m, 10H).

The above free compound (20 mg) was treated in a usual manner to givethe hydrochloride (23 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.19-1.23 (m,3H), 0.83-2.33 (m, 7H), 2.93 (s, 3H), 3.04-3.51 (m, 7H), 3.69-3.80 (m,5H), 4.40 (s, 2H), 7.30-7.46 (m, 10H).

ESI-Mass; 497 (MH+).

Example 58 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-isopropylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(benzylamino)ethyl]piperazine(67 mg) and isopropyl bromide (29.6 ml) were dissolved indimethylformamide (10 ml), then potassium carbonate (33.2 mg) was addedthereto, and the mixture was heated at 100° C. overnight. After thereaction mixture was cooled to room temperature, the organic layer waspartitioned by adding aqueous saturated sodium bicarbonate (7 ml) andethyl acetate, washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the title compound (15 mg, 20%) as a colorlessoil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 0.89 (m, 1H),0.99 (d, J=6.8 Hz, 6H), 1.10 (m, 1H), 1.19 (d, J=6.8 Hz, 3H), 1.26 (m,1H), 1.53 (m, 1H), 1.69 (m, 2H), 1.87 (td, J=4.4 Hz, 12.8 Hz, 1H),2.07-2.16 (m, 2H), 2.23-2.26 (m, 2H), 2.28-2.37 (m, 6H), 2.53-2.57 (m,2H), 2.90 (quintet, J=6.6 Hz, 1H), 3.57 (s, 2H), 7.20 (m, J=7.0 Hz, 1H),7.26-7.36 (m, 9H).

The above free compound (15 mg) was treated in a usual manner to givethe hydrochloride (18 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 0.86 (m, 1H),1.11 (d, J=6.4 Hz, 3H), 1.23 (m, 1H), 1.31 (d, J=6.0 Hz, 6H), 1.62 (m,1H), 2.11 (m, 1H), 2.22 (m, 1H), 2.67-3.44 (m, 13H), 4.35 (s, 2H), 7.37(m, 1H), 7.44 (m, 9H), 7.70 (m, 2H).

ESI-Mass; 462 (MH+).

Example 59 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine59-1)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(t-butoxycarbonyl)piperazine

The title compound (671 mg, 89%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (400 mg) andN-(t-butoxycarbonyl)piperazine (346 mg) in the same manner as in Example1.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.76 (d, J=6.8 Hz, 3H), 1.08-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 1.50-1.60 (m, 1H), 1.87-1.95(m, 1H), 2.08-2.31 (m, 8H), 3.35-3.40 (m, 4H), 7.16-7.31 (m, 5H).

59-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine

4 N HCl/ethyl acetate (20 ml) was added to1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(t-butoxycarbonyl)piperazine (671mg), and the mixture was stirred at 50° C. for 3 hours. The reactionmixture was evaporated, then saturated sodium bicarbonate was addedthereto, and the product was extracted with ethyl acetate. The organiclayer was washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the title compound (377 mg, 76%) as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.07-1.17 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.89 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.07-2.32 (m, 8H), 2.83 (t, J=5 Hz, 4H), 7.27-7.38 (m,5H).

59-3)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine (114 mg),3-chloro-4-fluoropropiophenone (75 mg) and triethylamine (0.06 ml) weredissolved in tetrahydrofuran (3 ml), and the mixture was stirredovernight at room temperature. The reaction mixture was diluted withethyl acetate, washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the free compound (99 mg, 56%) of the titlecompound as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.89 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.56 (m, 12H), 2.80 (t, J=7.6 Hz, 2H), 3.14 (t,J=7.6 Hz, 2H), 7.13 (t, J=8.4 Hz, 2H), 7.26-7.37 (m, 5H), 7.97 (dd,J=5.4 Hz, 8.4 Hz, 2H).

The above free compound (30 mg) was treated in a usual manner to givethe hydrochloride (39 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.8 Hz, 3H), 1.10 (d,J=6.8 Hz, 3H), 1.55-1.65 (m, 1H), 2.00-2.25 (m, 3H), 3.25-3.70 (m, 14H),7.33-7.44 (m, 7H), 8.05 (dd, 5.8 Hz, 8.2 Hz, 2H).

ESI-Mass; 436 (MH+).

Example 60 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-hydroxy-3-(4-flurophenyl)propyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine(64 mg) was dissolved in ethanol (1 ml), then sodium borohydride (65 mg)was added thereto, and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was diluted with ethyl acetate, washedwith water, dried, and evaporated. The residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem) to give the free compound of the title compound (64 mg,quantitative) as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.08-1.18 (m,1H), 1.20 (d, J=6.4 Hz, 3H), 1.50-1.60 (m, 1H), 1.79 (dd, J=6.6 Hz, 11Hz, 2H), 3.76 (dt, J=4 Hz, 13 Hz, 1H), 2.08-2.76 (m, 14H), 4.88 (t,J=5.6 Hz, 1H), 7.01 (t, J=8.8 Hz, 2H), 7.27-7.37 (m, 7H).

The above free compound was treated in a usual manner to give thehydrochloride (60 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.4 Hz, 3H), 1.15-1.28 (m, 1H), 1.52-1.67 (m, 1H), 1.90-2.22 (m, 5H),2.95-3.80 (m, 12H), 4.64 (q, 4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H),7.33-7.45 (m, 7H).

ESI-Mass; 438 (MH+).

Example 61 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxyl)acetyl]piperazine

Thionyl chloride (4 ml) was added to 4-fluorophenoxy acetic acid (3.52g) and heated under reflux for 1 hour. The reaction mixture wasevaporated, and the residual tetrahydrofuran (5 ml) solution was addedunder ice-cooling to a solution of 1-benzyl piperazine (3.65 g) andtriethylamine (2.9 ml) in tetrahydrofuran (15 ml), followed by stirringfor 1 hour at room temperature. The reaction mixture was diluted withethyl acetate, washed with water, dried, and evaporated. The residue wasdissolved in ethanol (60 ml), then conc. hydrochloric acid (3 ml) and10% palladium/carbon catalyst (1.3 g) were added thereto, and themixture was stirred overnight at room temperature in a hydrogenatmosphere. After the catalyst was filtered off, the filtrate wasevaporated, basified with 2 N aqueous NaOH, and extracted with ethylacetate. The organic layer was washed with water, dried, and evaporated.The residue was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(4.09 g, 83%) as a pale brown oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.82-2.87 (m, 4H), 3.54 (t, J=5.2 Hz,2H), 3.60 (t, J=5.2 Hz, 2H), 4.66 (s, 2H), 6.88-7.00 (m, 4H).

61-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)acetyl]piperazine

The free compound (140 mg, 98%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-phenyl) pentane nitrile (70mg) and 2-(4-fluorophenoxy)acetylpiperazine (78 mg) in the same manneras in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.06-1.17 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.48-1.60 (m, 2H), 1.89 (dt, J=4.4 Hz, 13.2Hz, 1H), 2.07-2.20 (m, 3H), 2.22-2.32 (m, 4H), 3.48-3.64 (m, 4H), 4.63(s, 2H), 6.70-6.80 (m, 2H), 6.85-7.00 (m, 2H), 7.28-7.34 (m, 1H),7.34-7.38 (m, 4H).

The above free compound (140 mg) was treated in a usual manner to givethe hydrochloride (142 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.12 (d,J=6.6 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.70 (m, 1H), 2.00-2.30 (m, 3H),2.78-2.90 (m, 1H), 2.90-3.18 (m, 3H), 3.40-3.53 (m, 1H), 3.95 (br-d,J=12.6 Hz, 1H), 4.33 (br-d, J=12.6 Hz, 1H), 4.75-4.90 (m, 2H), 6.90-6.97(m, 2H), 7.07-7.15 (m, 2H), 7.33-7.41 (m, 1H), 7.41-7.50 (m, 4H), 10.6(m, 1H). ESI-Mass; 438 (MH+).

Example 62 Synthesis of 1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-hydroxy-3-(4-fluorophenoxyl)propyl]piperazine 62-1)4-Fluorophenoxy Glycidyl Ether

4-Fluorophenol (3.0 g) was dissolved in dimethylformamide (50 ml), thensodium hydride (1.28 g, 50%) was added thereto, and the mixture wasstirred for 45 minutes in an ice bath. Epibromohydrin (2.3 ml) was addedto the reaction mixture, and the mixture was stirred for 3 hours in theice bath. The organic layer was partitioned by adding water and diethylether, and the resulting organic layer was washed with water and brine,dried, and evaporated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system) to give the free compound(3.4 g, 75%) of the title compound as a colorless oil.

Free Compound;

¹H-NMR (4 00 MHz, CDCl₃); δ (ppm) 2.75 (dd, J=5.6, 3.2 Hz, 1H),2.88-2.92 (m, 1H), 3.32-3.37 (m, 1H), 3.91 (dd, J=5.6, 11.2 Hz, 1H),4.20 (dd, J=3.2, 11.2 Hz, 1H).

62-2)1-(t-Butoxy)carbonyl-4-[2-hydroxy-3-fluorophenoxy)propyl]piperazine

1-(t-Butoxycarbonyl)piperazine (1.8 g) and 4-fluorophenoxy glycidylether (1.6 g) were dissolved in 2-propanol (50 ml) and stirred for 2hours under reflux. The solvent was evaporated, and the residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem) to give the free compound (2.48 g, 74%) of the title compound asa colorless solid.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.47 (s, 9H), 2.35-2.45 (m, 2H),12.50-2.58 (m, 2H), 2.58-2.66 (m, 2H), 3.36-3.56 (m, 2H), 3.72-4.00 (m,2H), 4.06-4.14 (m, 1H), 6.84-6.90 (m, 2H), 6.94-7.01 (m, 2H).

62-3) 1-[2-Hydroxy-3-(4-fluorophenoxy)propyl]piperazine Trifluoacetate

1-(t-Butoxycarbonyl)-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine(520 mg) was dissolved in dichloromethane (5 ml), and trifluoroaceticacid (0.5 ml) was added thereto under ice-cooling, and the mixture wasstirred for 2 hours. After the solvent was concentrated, toluene wasadded thereto, and the reaction mixture was evaporated again to give thetrifluoroacetate (450 mg) of the title compound.

Trifluoroacetate;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 3.20-3.60 (m, 12H), 3.95 (d, J=4.8Hz, 2H), 4.26 (m, 1H), 6.95-7.01 (m, 2H), 7.12-7.18 (m, 2H).

62-4)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine

The free compound (124 mg, 74%) of the title compound was obtained as acolorless oil in the same manner as in Example 1 from2-(t-methylethyl)-5-oxo-2-phenyl pentane nitrile (80 mg),1-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine, and thetrifluoroacetate (274 mg) obtained in item 3) above.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.21 (d, J=6.6 Hz, 3H), 1.50-1.80 (m, 3H), 1.80-2.20 (m, 3H),2.20-2.60 (m, 7H), 2.60-2.70 (m, 2H), 3.92 (d, J=5.6 Hz, 2H), 4.04 (m,1H), 6.83-6.88 (m, 2H), 6.92-7.00 (m, 2H), 7.27-7.33 (m, 1H), 7.34-7.40(m, 4H).

The above free compound (124 mg) was treated in a usual manner to givethe hydrochloride (110 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=5.6 Hz, 3H), 1.11 (d,J=5.6 Hz, 3H), 1.60-1.70 (m, 1H), 2.00-2.15 (m, 3H), 3.00-3.90 (m, 12H),3.90-4.00 (2H, m), 4.28 (m, 1H), 6.94-7.02 (m, 2H), 7.08-7.18 (m, 2H),7.30-7.50 (m, 5H).

ESI-Mass; 454 (MH+).

Example 63 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine63-1) N-Acryloyl-4-fluoroaniline

4-Fluoroaniline (7 ml) and acryloyl chloride (7.2 ml) were dissolved intetrahydrofuran (100 ml), then triethylamine (15 ml) was added thereto,and the mixture was stirred overnight at room temperature. The organiclayer was partitioned by adding aqueous saturated sodium bicarbonate andethyl acetate, and the organic layer was washed with water and driedover sodium sulfate anhydrous, and after the drying agent was filteredoff, the filtrate was evaporated, whereby the title compound (12.2g,100%) was obtained as pale yellow solid.

¹H -NMR (400 MHz, CDCl₃); δ (ppm) 5.76-5.79 (m, 1H), 6.24 (dd, J=10.4,16.8 Hz, 1H), 6.14-6.50 (m, 1H), 7.01-7.06 (m, 2H), 7.14 (m, 1H),7.53-7.54 (m, 2H).

63-2) 1-Benzyl-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine

N-Acryloyl-4-fluoroaniline (12.2 g) and 1-benzyl piperazine (19.7 g)were dissolved in methanol (150 ml), and the mixture was stirredovernight at room temperature. The reaction mixture was evaporated, andthe residue was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(25 g, 100%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.51 (t, J=5.8 Hz, 2H), 2.63 (br-s,8H), 2.72 (t, J=5.8 Hz, 2H), 3.59 (s, 2H), 7.01 (m, J=8.8 Hz, 2H),7.25-7.35 (m, 5H), 7.46-7.50 (m, 2H), 11.1 (br-s, 1H).

63-3) [2-(4-Fluorophenylaminocarbonyl)ethyl]piperazine

1-Benzyl-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine (2.9 g) wasdissolved in acetic acid (100 ml), then 10% palladium carbon (7.2 g) wasadded thereto, and the mixture was stirred overnight in a hydrogenatmosphere. The 10% palladium carbon was filtered off, and the filtratewas evaporated, and water was added to the residue which was thenbasified by adding 1 N aqueous sodium hydroxide and subjected toextraction with chloroform, and the organic layer was washed with water,dried, and evaporated, whereby the title compound (1.5 g, 70%) wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.84 (br-s, 2H), 2.53 (t, J=5.8 Hz,2H), 2.60 (m, 4H), 2.72 (t, J=5.8 Hz, 2H), 3.01 (t, J=4.8 Hz, 2H), 7.00(m, J=8.8 Hz, 2H), 7.48-7.52 (m, 2H), 11.1 (br-s, 1H).

63-4)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine

The title compound (163 mg, 62%) was obtained as a colorless oil from2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (126 mg) and[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine (176 mg) in the samemanner as in Example 66.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.18 (m, 1H)1.21 (d, J=6.8 Hz, 3H), 1.58 (m, 1H), 1.78 (m, 1H), 1.92 (td, J=13.0 Hz,4.4 Hz, 1H), 2.13 (quintet, J=6.8 Hz, 1H), 2.15-2.21 (m, 1H), 2.26-2.38(m, 3H), 2.44 (br-s, 3H), 2.50 (t, J=6.0 Hz, 2H), 2.58 (br-s, 3H), 2.70(t, J=6.0 Hz, 2H), 6.99 (m, J=8.8 Hz, 2H), 7.30 (m, 1H), 7.35-7.39 (m,4H), 7.46 (dd, J=4.8 Hz, 6.8 Hz, 1H), 7.47 (dd, J=4.8 Hz, 7.0 Hz, 1H),11.1 (br-s, 1H).

The above free compound (100 mg) was treated in a usual manner to givethe hydrochloride (189 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.26 (m, 1H), 1.59-2.45 (m, 5H), 2.23 (t, J=6.8 Hz, 1H),2.54-3.86 (m, 13H), 7.15 (t, J=8.8 Hz, 2H), 7.37 (m, 1H), 7.44-7.46 (m,4H), 7.58-7.62 (m, 2H).

ESI-Mass; 451 (MH+).

Example 64 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoylamino)ethyl]piperazine64-1) 1-[2-(4-fluorobenzoylamino)]-4-(t-butoxycarbonyl)piperazine

The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (1.33 g) obtained inExample 58 and 4-fluorobenzoyl chloride (1.1 g) were dissolved intetrahydrofuran (20 ml), then triethylamine (1.6 ml) was added thereto,and the mixture was stirred overnight at room temperature. The organiclayer was partitioned by adding aqueous saturated sodium bicarbonate andethyl acetate, and the organic layer was washed with water, dried, andevaporated. The residue was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(1.42 g, 70%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.47 (s, 9H), 2.44-2.26 (m, 4H), 2.62(t, J=6.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 4H), 3.54-3.56 (m, 2H), 6.71 (m,1H), 7.12 (m, J=8.6 Hz, 2H), 7.77-7.81 (m, 2H).

64-2)1-[(4-Cyano-9-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoylamino)ethyl]piperazine

The title compound (102 mg, 40%) was obtained as a colorless oil from1-[2-(4-fluorobenzenesulfonylamino)ethyl]-4-(t-butoxycarbonyl)piperazine(159 mg) in the same manner as in Example 66.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.13 (m, 1H),1.20 (d, J=6.8 Hz, 3H), 1.56 (m, 1H), 1.78-1.94 (m, 3H), 2.09-2.19 (m,2H), 2.23-2.33 (m, 2H), 2.34 (m, 3H), 2.48 (m, 3H), 2.58 (t, J=6.2 Hz,2H), 3.51 (t, J=5.6 Hz, 2H), 6.76 (br-s, 1H), 7.11 (m, J=8.8 Hz, 2H),7.29 (m, 1H), 7.32-7.38 (m, 4H), 7.75-7.80 (m, 2H).

The above free compound (100 mg) was treated in a usual manner to givethe hydrochloride (116 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.12 (d,J=6.8 Hz, 3H), 1.24-1.27 (m, 1H), 2.09-2.19 (m, 2H), 2.22 (d, J=6.6 Hz,1H), 3.42 (br-s, 17H), 3.65 (m, 1H), 7.32 (t, J=8.8 Hz, 2H), 7.37 (m,1H), 7.43-7.46 (m, 4H), 7.95-7.99 (m, 2H).

ESI-Mass; 451 (MH+).

Example 65 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine65-1) 1-Benzyl-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine

N-Chloroacetyl-4-fluoroaniline (15.18 g), 1-benzyl piperazine (18.94 g)and triethylamine (15 ml) were dissolved in dimethylformamide (200 ml),and the mixture was stirred overnight at room temperature. The reactionmixture was evaporated, and ethyl acetate was added thereto. The organiclayer was washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the title compound (23.32 g, 86%) as pale brownsolid.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.48-2.60 (m, 4H), 2.62-2.68 (m, 4H),3.13 (s, 2H), 3.55 (s, 2H), 7.02 (t, J=8.8 Hz, 2H), 7.24-7.34 (m, 5H),7.53 (dd, J=4.8 Hz, 8.8 Hz, 2H), 9.10-9.15 (br-s, 1H).

65-2) 4-[N-(4-Fluorophenyl)carbamoylmethyl]piperazine

1-Benzyl-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine (6.07 g) wasdissolved in ethanol (100 ml), then 10% palladium/carbon catalyst (1.3g) was added thereto, and the mixture was stirred overnight at roomtemperature in a hydrogen atmosphere. After the catalyst was filteredoff, the filtrate was evaporated, and the residue was purified byCromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (4.21 g, 96%) was obtained as a palebrown oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.59 (t, J=1.8 Hz, 4H), 2.96 (t, J=4.8Hz, 4H), 3.11 (s, 2H), 7.03 (t, J=8.8 Hz, 2H), 7.53 (dd, J=4.8 Hz, 8.8Hz, 2H), 9.10-9.16 (br-s, 1H).

65-3)1-(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine

The free compound (183 mg, 84%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (109mg) and 4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine (120 mg) in thesame manner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.4 Hz, 3H), 1.09-1.19 (m,1H), 1.21 (d, J=6.8 Hz, 3H), 1.50-1.61 (m, 1H), 1.91 (ddd, J=4.4 Hz,12.2 Hz, 13.4 Hz, 1H), 2.09-2.45 (m, 8H), 2.56-2.63 (br-s, 4H), 3.10 (m,2H), 7.01 (t, 8.8 Hz, 2H), 7.27-7.38 (m, 5H), 7.51 (dd, J=4.8 Hz, 8.8Hz, 2H), 9.07 (s, 1H).

The above free compound was treated in a usual manner to give thehydrochloride (182 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.66 (d, J=6.4 Hz, 3H), 1.10 (d,J=6.8 Hz, 3H), 1.18-1.30 (m, 1H), 1.56-1.68 (m, 1H), 2.03-2.23 (m, 3H),3.00-3.90 (m, 13H), 7.16 (t, J=8.8 Hz, 2H), 7.33-7.44 (m, 5H), 7.61 (dd,J=5.2 Hz, 8.8 Hz, 2H).

ESI-Mass; 437 (MH+).

Example 66 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine66-1)1-[2-(4-Fluorobenzenesulfonylamino)ethyl]-4-t-butoxycarbonyl)piperazine

The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (2.01 g) obtained inExample 58 and 4-fluorobenzene sulfonyl chloride (2.05 g) were dissolvedin tetrahydrofuran (20 ml), and triethylamine (2.4 ml) was addedthereto, and the mixture was stirred overnight at room temperature.Water (50 ml) was added to the reaction mixture which was then extractedwith ethyl acetate, and the organic layer was washed with water, dried,and evaporated. The residue was purified by Cromatorex NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound (2.61 g, 77%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.45 (s, 9H), 2.23 (t, J=5.2 Hz, 4H),2.42-2.45 (m, 2H), 2.99-3.03 (m, 2H), 3.35 (t, J=5.2 Hz, 4H), 5.17 (m,1H), 7.20 (m, J=8.6 Hz, 2H), 7.22-7.37 (m, 2H).

66-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine

1-[2-(4-Fluorobenzenesulfonylamino)ethyl]-4-(t-butoxycarbonyl)piperazine(260 mg) was dissolved in dichloromethane (2.0 ml), and trifluoroaceticacid (2 ml) was added thereto under stirring at 0° C., and the mixturewas stirred at 0° C. for 1 hour. The reaction mixture was evaporated.The residue was dissolved in dichloroethane (10 ml), and2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (177 mg), acetic acid(0.10 ml) and sodium triacetoxy borohydride (261 mg) were added thereto,and the title compound (247 mg, 62%) was obtained as a colorless oil inthe same manner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃) δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.11 (m, 1H),1.21 (d, J=6.8 Hz, 3H), 1.53 (m, 1H), 1.74-1.91 (m, 2H), 1.96-2.19 (m,2H), 2.25-2.45 (m, 10H), 2.39 (t, J=5.8 Hz, 2H), 2.98 (t, J=5.8 Hz, 2H),7.16-7.23 (m, 2H), 7.29 (m, 1H), 7.34-7.39 (m, 4H), 7.85-7.91 (m, 2H).

The above free compound (166 mg) was treated in a usual manner to givethe hydrochloride (191 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 1.11 (d, J=6.4 Hz, 3H), 1.25 (m, 1H), 1.62 (m, 1H), 2.06-2.24 (m, 3H), 3.17-3.21 (m,6H), 3.33-3.51 (m, 10H), 7.33-7.39 (m, 1H), 7.41-7.49 (m, 6H), 7.89 (dd,J=5.2 Hz, 6.8 Hz, 1H), 7.91 (dd, J=5.2 Hz, 7.2 Hz, 1H), 8.12 (br-s, 1H).

ESI-Mass; 487 (MH+).

Example 67 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)sulfamoyl]ethyl}piperazine67-1)1-{2-[N-(4-fluorophenyl)sulfamoyl]ethyl}-4-(t-butoxycarbonyl)piperazine

A solution of 4-fluoroaniline (3.41 g) and triethylamine (4.5 ml) intetrahydrofuran (20 ml) was added dropwise to a solution of2-chloroethane sulfonyl chloride (5 g) in tetrahydrofuran (50 ml) underice-cooling, and the mixture was stirred for 1 hour at room temperature.5 N aqueous NaOH was added thereto, followed by extraction with ethylacetate. The organic layer was washed with water, dried, and evaporated.A part (3.81 g) of the residue (5.56 g) andN-(t-butoxycarbonyl)piperazine (2.3 g) were dissolved in methylenechloride (20 ml) and stirred at room temperature for 2 hours. Thereaction mixture was evaporated and purified by Cromatorex NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound (6.01 g, 82%) was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.46 (s, 9H), 2.46 (t, J=5 Hz, 4H),2.92 (t, J=6.4 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 3.44 (t, J=5 Hz, 4H),7.05 (t, J=8.6 Hz, 2H), 7.17-7.21 (m, 2H).

67-2) 1-{2-[N-(4-Fluorophenyl]ethyl}piperazine

1-{2-[N-(4-Fluorophenyl)sulfonyl]ethyl}-4-(t-butoxycarbonyl)piperazine(6.01 g) was dissolved in ethanol (10 ml), then 4 N HCl/ethyl acetate(40 ml) was added thereto, and the mixture was stirred at 50° C. for 4hours. The reaction mixture was evaporated, neutralized with 5 N aqueousNaOH, and extracted with chloroform. The organic layer was washed withwater, dried, and evaporated, whereby the title compound (3.52 g, 79%)was obtained as a pale brown solid.

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 2.20-2.30 (m, 4H), 2.60-2.66 (m, 6H),3.19 (t, J=7.4 Hz, 2H), 7.15 (t, J=9.2 Hz, 2H), 7.22 (dd, J=4.8 Hz, 9.2Hz, 2H).

67-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-]N-(4-fluorophenyl)sulfonyl)ethyl}piperazine

The free compound (179 mg, 80%) of the title compound was obtained as apale yellow oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile(100 mg) and 1-[2-(4-fluorophenyl)propyl]piperazine (133 mg) in the samemanner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.4 Hz, 3H), 1.05-1.16 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.60 (m, 1H), 1.88 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.56 (m, 12H), 2.88 (t, J=6.4 Hz, 2H), 3.19 (t,J=6.4 Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 7.19 (dt, 4.4 Hz, 8.6 Hz, 2H),7.27-7.38 (m, 5H).

The above free compound (119 mg) was treated in a usual manner to givethe hydrochloride (120 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.8 Hz, 3H), 1.15-1.28 (m, 1H), 1.53-1.65 (m, 1H), 2.00-2.25 (m, 3H),2.95-3.75 (m, 14H), 7.17 (t, J=8.8 Hz, 2H), 7.25 (dt, J=4.8 Hz, 8.8 Hz,2H), 7.32-7.43 (m, 5H), 10.00 (s, 1H).

ESI-Mass; 487 (MH+).

Example 68 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylsulfamoyl]ethyl}piperazine

60% sodium hydride (10 mg) was added to a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4{2-[N-(4-fluorophenyl)sulfonyl]ethyl}piperazine(60 mg) in dimethylformamide (2 ml) under ice-cooling, and the mixturewas stirred for 30 minutes at room temperature. The reaction mixture wasagain ice-cooled, and methyl iodide (0.01 ml) was added thereto, and themixture was stirred for 1 hour. The reaction mixture was diluted withethyl acetate, washed with water, dried, and evaporated. The residue waspurified by Cromatorex NH silica gel column chromatography (hexane/ethylacetate system) to give the free compound (51 mg, 81%) of the titlecompound as a pale yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.16 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.58 (m, 1H), 1.88 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.48 (m, 12H), 2.79-2.82 (m, 2H), 3.12-3.15 (m,2H), 3.31 (s, 3H), 7.02 (t, J=8.6 Hz, 2H), 7.16 (t, 8.6 Hz, 2H),7.27-7.38 (m, 7H).

The above free compound was treated in a usual manner to give thehydrochloride (38 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.8 Hz, 3H), 1.09 (d,J=6.8 Hz, 3H), 1.18-1.3 (m, 1H), 1.55-1.68 (m, 1H), 2.03-2.23 (m, 3H),2.95-3.20 (m, 4H), 3.25 (s, 3H), 3.35-3.80 (m, 10H), 7.24 (t, J=8.8 Hz,2H), 7.32-7.43 (m, 5H), 7.49 (dd, J=4.8 Hz, 8.8 Hz, 2H).

ESI-Mass; 501 (MH+).

Example 69 Synthesis of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-fluorobenzenesulfonylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine(31 mg) was dissolved in dimethylformamide (5.0 ml), and sodium hydride(5.1 mg) and methyl iodide (0.01 ml) were added thereto at 0° C. understirring, and the mixture was stirred overnight at room temperature. Thereaction mixture was acidified by adding 5 M hydrochloric acid and thenevaporated. The residue was dissolved in dimethylformamide (5 ml), andthiourea (7.3 mg) was added thereto, and the mixture was heatedovernight under reflux. After the reaction mixture was cooled to roomtemperature, the organic layer was partitioned by adding water and ethylacetate, and the organic layer was washed with water, dried, andevaporated. The residue was purified by Cromatorex NH silica gel columnchromatography (hexane/ethyl acetate system) to give the title compound(13 mg, 41%) as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.08-1.14 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.25-1.55 (m, 3H), 1.88 (td, J=4.6,13.0 Hz,1H), 2.08-2.18 (m, 2H), 2.21-2.27 (m, 2H), 2.27-2.38 (br-s, 3H),2.38-2.48 (br-s, 3H), 2.52 (t, J=7.0 Hz, 2H), 2.78 (s, 3H), 3.13 (m,2H), 7.19 (m, J=8.4 Hz, 2H), 7.29 (m, 1H), 7.34-7.41 (m, 4H), 7.84-7.79(m, 2H).

The above free compound (13 mg) was treated in a usual manner to givethe hydrochloride (14.8 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77-0.81 (m, 3H), 0.86-0.90 (m, 1H),1.19-1.23 (m, 3H), 1.24-2.43 (m, 9H), 2.66-3.91 (m, 9H), 2.85 (m, 3H),7.26-7.42 (m, 7H), 7.84 (m, 2H).

ESI-Mass; 501.1 (MH+).

Example 70 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-fluorophenylthio)carbonyloxyl]ethyl}piperazine

The free compound (228 mg, 84%) of the title compound was obtained as acolorless oil from 2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (120mg) and S-(4-fluorophenyl) thiocarbonate.1-(1-piperazinyl)ethyl (159 mg)in the same manner as in Example 1.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.06-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.49-1.60 (m, 1H), 1.90 (ddd, J=4.4 Hz, 12Hz, 13.6 Hz, 1H), 2.08-2.28 (m, 8H), 3.09 (t, J=6.8 Hz, 2H), 3.28-3.44(m, 4H), 4.20 (t, J=6.8 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 7.26-7.41 (m,5H).

The above free compound was treated in a usual manner to give thehydrochloride (88 mg) of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.65 (d, J=6.4 Hz, 3H), 1.10 (d,J=6.4 Hz, 3H), 1.16-1.26 (m, 1H), 1.54-1.66 (m, 1H), 2.04-2.24 (m, 3H),2.78-3.37 (m, 13H), 4.10-4.18 (m, 2H), 7.17 (t, J=9 Hz, 2H), 7.33-7.37(m, 1H), 7.40-7.46 (m, 6H).

ESI-Mass; 484 (MH+).

Example 71 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (225mg) and 2-bromopyridine (0.10 ml) were dissolved in dimethylformamide(20 ml), then sodium hydride (45 mg) was added thereto at roomtemperature, and the mixture was stirred at 40° C. overnight. Sodiumhydride (45 mg) and 2-bromopyridine (0.20 ml) were further added to thereaction mixture, and the mixture was heated at 75° C. The reactionmixture was poured into aqueous sodium bicarbonate, extracted with ethylacetate, washed with water and brine, and dried. After evaporated, theresidue was purified by Cromatorex NH silica gel column chromatography(hexane/ethyl acetate system), whereby the free compound of the titlecompound was obtained as an oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.8Hz, 3H), 1.25-1.27 (m, 1H), 2.04-2.34 (m, 4H), 2.80-3.60 (m, 14H),6.71-6.76 (m, 1H), 6.85-6.91 (m, 1H), 7.27-7.34 (m, 1H), 7.35-7.42 (m,4H), 7.54-7.61 (m, 1H), 8.10-8.14 (m, 1H).

The above free compound was dissolved in methanol, and 4 N hydrogenchloride/ethyl acetate solution was added thereto. The solvent andexcess hydrogen chloride were evaporated and recrystallized frommethanol/ether, whereby the hydrochloride (55 mg) of the title compoundwas obtained.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.33 (m, 1H), 1.56-1.70 (m, 1H), 2.04-2.30 (m, 3H),3.00-3.82 (m, 14H), 4.61 (br-s, 2H), 6.86-6.90 (m, 1H), 7.02-7.07 (m,1H), 7.34-7.40 (m, 1H), 7.42-7.48 (m, 4H), 7.73-7.79 (m, 1H), 8.17-8.20(m, 1H).

ESI-Mass; 407 (MH⁺).

Example 72 Synthesis of1-(3-Cyclohexyl-3-cyano-3-phenyl)propionyl-4-[2-(4-fluorophenoxy)ethyl]piperazine

Cyclohexyl phenyl acetonitrile (1.99 g) synthesized according to J.M.C.,35, 2210-2214, 1992, and sodium hydride (370 mg, 65%) were dissolved indimethylformamide (35 ml), and the mixture was stirred at 60° C. for 3hours. The reaction mixture was allowed to reach room temperature, andethyl brome acetate (1.67 g) and tetrahydrofuran (4 ml) were addedthereto, and the mixture was stirred overnight at 60 to 70° C. Theorganic layer was partitioned by adding water and an ether/hexane mixedsolvent, washed with water, dried, and evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby ethyl 3-cyano-3-phenyl-3-cyclohexyl propionate (1.13 g)was obtained as a colorless oil.

Ethanol (16 ml) and 8 N sodium hydroxide (2.0 ml) were added thereto,and the mixture was stirred overnight at room temperature. Afterneutralized with 5 N hydrochloric acid, the organic layer waspartitioned by adding ether/ethyl acetate, washed with water, dried, andevaporated to give 3-cyano-3-phenyl-3-cyclohexyl propionic acid (940mg).

This carboxylic acid (205 mg) was dissolved in tetrahydrofuran (4.0 ml),and dimethylformamide (2 drops) and oxazalyl chloride (120 mg) wereadded thereto, and the mixture was stirred for 10 minutes at roomtemperature and then evaporated. The residue was dissolved intetrahydrofuran (3.0 ml) and added to a solution of previously prepared1-[2-(4-fluorophenoxy)ethyl]piperazine (215 mg) and triethylamine (120mg) in tetrahydrofuran (5.0 ml). After stirred for 3 hours, the organiclayer was partitioned by adding aqueous saturated sodium bicarbonate andethyl acetate, washed with water, dried, and evaporated. The residue waspurified by silica gel column chromatography (hexane-ethylacetate/methanol system), whereby the title compound (160 mg) wasobtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.05-1.40 m, 5H), 1 .60-1.70 (m, 3H),1.83-1.90 (m, 1H), 1.95-2.15 (m, 2H), 2.30-2.45 (m, 4H), 2.77 (t, J=5.8Hz, 2H), 3.01 (d, J=5 Hz, 2H), 3.13 (d, J=5 Hz, 2H), 3.20-3.35 (m, 2H),3.42-3.50 (m, 2H), 4.04 (t, J=5.8 Hz, 2H), 6.80-6.85 (m, 2H), 6.91-6.99(m, 2H), 7.22-7.43 (m, 4H).

Example 73 Synthesis of1-(2-Hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenoxy)ethyl]piperazine73-1) (3-Methyl-2-cyano-2-phenyl)butyl Oxirane

3-Methyl-2-phenylbutyronitrile (4.19 g) synthesized according toJ.Chem.Soc. Perkin Trans, 1, 2845-2850, 1996, and 65% oily sodiumhydride (1.05 g) were dissolved in dimethylformamide (90 ml), and themixture was stirred at 60° C. for 3 hours. The reaction mixture wasallowed to reach room temperature, and allyl bromide (2.9 g) andtetrahydrofuran (3.0 ml) were added thereto, and the mixture was stirredovernight at 60° C. The organic layer was partitioned by adding waterand an ether/hexane mixed solvent, washed with water, dried, andevaporated. The residue was purified by silica gel column chromatography(hexane/ethyl acetate system), whereby(5-methyl-4-cyano-4-phenyl)-1-hexene (4.5 g, 86 %) was obtained as acolorless oil.

This product (2.5 g) was dissolved in dichloromethane (60 ml), andsodium bicarbonate (2.35 g) and m-chloroperbenzoic acid (2.76 g) wereadded thereto under ice-cooling, and the .mixture was stirred overnightat room temperature. Ethanol (16 ml) and 8 N sodium hydroxide (2.0 ml)were added thereto, and the mixture was stirred overnight at roomtemperature. Aqueous saturated sodium bicarbonate and dichloromethanewere added to the reaction mixture, and the organic layer waspartitioned, washed with water, dried, and evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the early eluted diastereomer (800 mg, 30%) of thetitle compound and the late eluted diastereomer (390 mg, 14%) of thetitle compound were obtained.

Diastereomer 1 (eluted early)

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.81 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.8Hz, 3H), 2.05 (dd, J=7.2 Hz, 14 Hz, 1H), 2.16-2.24 (m, 1H), 2.44 (dd,J=12.8 Hz, 17.2 Hz, 1H), 2.58-2.64 (m, 1H), 2.64-2.68 (m, 1H), 2.70-2.74(m, 1H), 7.30-7.50 (m, 5H).

Diastereomer 2 (eluted late)

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.81(d, J=6.8 Hz, 3H), 1.22 (d, J=6.8Hz, 3H), 1.92 (dd, J=6.4Hz, 14.4 Hz, 1H), 2.17-2.26 (m, 1H), 2.48-2.78(m, 1H), 2.64-2.68 (m, 2H), 2.810-2.874 (m, 1H), 7.30-7.50 (m, 5H).

73-2)1-(4-Hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenoxyl)ethyl]piperazine

The early eluted diastereomer 1 (390 mg),1-[2-(4-fluorophenoxy)ethyl]piperazine (450 mg), and ytterbium IIItrifluoromethane sulfonic acid monohydrate (90 mg) were added todichloromethane (2.5 ml), and the mixture was stirred overnight at roomtemperature. The solvent was evaporated, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate/methanol system)to give the title compound (320 mg, 40%).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.76 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.8Hz, 3H), 2.10-2.24(m, 3H), 2.27-2.43 (m, 3H), 2.43-2.51 (m, 7H), 2.73(t, J=6.0 Hz, 2H), 3.48-3.55 (m, 1H), 4.03 (t, J=6.0 Hz, 2H),6.79-6.85(m, 2H), 6.92-6.98 (m, 2H), 7.26-7.34 (m, 1H), 7.34-7.40 (m,4H).

Example 74 Systhesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzylphenoxy)ethyl]piperazine

N-[2-(Benzylphenoxy)ethyl]piperazine (169.9 mg),2-(1-methylethyl)-5-oxo-2-phenyl pentane nitrile (103 mg), and aceticacid(0.05 ml) were dissolved in dichloroethane (5 ml), then sodiumtriacetoxy borohydride (160 mg) was added thereto, and the mixture wastreated in the same manner as in Example 1, whereby the free compound(96 mg, 41%) of the title compound was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.2 Hz, 3H), 1.06-1.53 (m,1H), 1.20 (d, J=6.2 Hz, 3H), 1.50-1.61 (m, 1H), 1.77 (m, 1H), 1.88 (td,J=4.4 Hz, 12.6 Hz, 1H), 1.95-2.31 (m, 7H), 2.50 (br-s, 4H), 2.75 (t,J=5.6 Hz, 2H), 3.06 (s, 2H), 4.06 (t, J=5.6 Hz, 2H), 6.83 (d, J=8.4 Hz,1H), 6.88 (t, J=7.4 Hz, 1H), 7.08-7.32 (m, 8H), 7.34-7.39 (m, 4H).

The above free compound (96 mg) was treated in a usual manner to givethe hydrochloride (110 mg) of the title compound as a colorlessamorphous.

Hydrochloride;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79(d, J=6.4 Hz, 3H), 1.24 (d, J=6.4Hz, 3H), 1.25 (m, 1H), 1.43 (m, 1H), 1.78 (m, 1H), 2.04 (m, 1H), 2.16(m, 2H), 2.33 (m, 1H), 2.87 (m, 1H), 2.90-3.10 (m, 2H), 3.25 (m, 1H),3.35 (m, 2H), 3.46 (m, 2H), 3.70 (m, 2H), 4.00 (s, 2H), 4.43 (m, 2H),6.84 (d, J=6.8 Hz, 1H), 7.00-7.07 (m, 5H), 7.19-7.20 (m, 2H), 7.36-7.44(m, 6H).

ESI-Mass; 496 (MH+).

Finally, experimental examples where the compound in Example 1 wasoptically resoluted by optically active column HPLC are described asPreparatory Examples for obtaining optically active substances in thepresent invention. (Refer to FIG. 8).

HPLC analysis conditions

Solid phase: chiralcel OJ (0.46 cm × 25 cm, Daicel Chemical) Mobilephase: n-hexane:isopropyl alcohol:ethanol = 850:100:50 Flow rate: 0.5ml/min Temperature: 25° C. Detector: UV 210 nm

Example 75(−)-1-[(4-Cyano-5-methyl-4-phehnyl)hexyl]-4-[2-fluorophenoxyl)ethyl]piperazinehydrochloride

The title compound was obtained as the early eluted fraction in the HPLCexperimental example described above.

[α]²⁹ _(D)=−5.18 (C=1.0, ethanol)

Example 76(+)-1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazineHydrochloride

The title compound was obtained as the late eluted fraction in the HPLCexperimental example described above.

[α]³⁰ _(D)=+6.23 (C=1.0, ethanol)

In the same manner, optically active substances were separated from thecompound of Example 25.

Example 77(−)-1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazineHydrochloride

[α]^(27.8) _(D)=−6.552 (C=0.250, ethanol)

Example 78(+)-1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazineHydrochloride

[α]^(27.6) _(D)=+4.118 (C=0.267, ethanol)

In the same manner, optically active substances were separated from thecompound of Example 38.

Example 79(−)-1-[(4-Cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazineHydrochloride

[α]27.4_(D)=−5.717 (C=1.833, ethanol)

Example 80(+)-1-[(4-Cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazineHydrochloride

[α]^(28.2) _(D)=+4.792 (C=0.250, ethanol)

Example 81 Synthesis of1-[(4-Cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazine81-1) Ethyl 5-Benzyloxy-2-cyano-2-phenylpetanoate

Sodium hydride was added to a solution of ethyl phenylcyanoacetate 3 gin dimethylformaldehyde 20 ml under ice-cooling, and the mixture wasstirred at room temperature for 1 hour. It was ice-cooled again,benzyl-3-bromopropyl ether (4.2 ml) was added thereto, and the mixturewas stirred at room temperature for 3 hours. After the reaction mixturewas evaporated, water was added thereto and the product wasextractedwithethylacetate. The organic layer was washed with water,dried, and evaporated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(2.892 g, 54%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.22 (t, J=7.2 Hz, 3H), 1.65-1.84 (m,2H), 2.23-2.31 (m, 1H), 2.44-2.51 (m, 1H), 3.49 (t, J=6.2 Hz, 2H),4.14-4.26(m, 2H), 4.46 (s, 2H), 7.23-7.41 (m, 8H), 7.54-7.56 (m, 2H).

81-2) 5-Benzyloxy-2-(1-hydroxy-1-methylethyl)-2-phenylpentanenitrile

3M-methyl magnesium bromide in ether 8 ml was added dropwise to asolution of ethyl 5-benzyloxy-2-cyano-2-phenyl pentanoate 2.892 g inether 30 ml under ice-cooling, and the mixture was stirred for 1 hour.Aqueous saturated ammonium chloride was added to the reaction mixturewhich was then extracted with ethyl acetate. The organic layer waswashed with brine, dried, and evaporated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate system) wherebythe title compound (1.658 g, 60%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.22 (s, 3H), 1.35-1.45 (m, 1H), 1.37(s, 3H), 1.67-1.77 (m, 1H), 2.17-2.25 (m, 1H), 2.38-2.45 (m, 1H), 3.47(t, J=6.2 Hz, 2H), 4.45 (s, 2H), 7.24-7.39 (m, 8H), 7.46-7.51 (m, 2H).

81-3) 2-(1-Hydroxy-1-methylpthyl)-5-ioin-2-phenylpentanenitrile

10%-palladium/carbon catalyst 250 mg was added to a tes o lution of5-benzyloxy-2-(1-hydroxy-1-methylethyl)-2-phenylpentanenitrile 1.658 gin ethanol 20 ml, and the mixture was stirred in a hydrogen atmospherefor 5 hours. After the catalyst was filtered off, the filtrate wasevaporated. The residue and triethylamine 1.1 ml were dissolved intetrahydrofuran 15 ml, and methane sulfonyl chloride 0.6 ml was addedthereto under ice-cooling, and the mixture was stirred at roomtemperature for 30 minutes. Water was added to the reaction mixturewhich was then extracted with ethyl acetate, and the organic layer waswashed with water, dried, and evaporated. The residue was dissolved inacetone 40 ml, and sodium iodide 3.9 g was added thereto, and themixture was heated under reflux for 2 hours. The reaction mixture wasevaporated, water was added thereto, and the product was extracted withethyl acetate. The organic layer was washed with water, dried, andevaporated, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound1.493 g, 85% was obtained as a yellowish brown oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.25 (s, 3H), 1.42 (s, 3H), 1.50-1.60(m, 1H), 1.91-2.01 (m, 1H), 2.20-2.27 (m, 1H), 2.45-2.52 (m, 1H),3.12-3.26 (m, 2H), 7.36-7.44(m, 1H), 7.47-7.51 (m, 2H).

81-4)1-[(4-Cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-fluorophenoxyl)ethyl]piperazine

1-[2-(4-fluorophenoxy)ethyl]piperazine 359 mg and triethylamine 0.22 mlwere added to a solution of2-(1-hydroxy-1-methylethyl)-5-iodo-2-phenylpentanenitrile 545 mg intetrahydrofuran 7 ml, and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate, washedwith water, dried, and evaporated. The residue was purified byChromatorex NH silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (406 mg, 56%) was obtained as acolorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.24 (s, 3H), 1.39 (s, 1H), 1.57-1.72(m, 2H), 2.12-2.19 (m, 1H), 2.28-2.70 (m, 11H), 2.78 (t, J=6 Hz, 2H),4.04 (t, J=6 Hz, 2H), 6.81-6.85 (m, 2H), 6.93-6.99 (m, 2H), 7.32-7.42(m, 3H), 7.46-7.50 (m, 2H).

The above free compound 125 mg was treated in a usual manner to give thehydrochloride 131 mg of the title compound.

Hydrochloride;

ESI-Mass; 440 (MH+).

Example 82 Synthesis of1-[5-(4-Cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-fluorophenoxyl)ethyl]piperazine

1-[(4-Cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine145 mg was dissolved in thionyl chloride 1 ml and heated under refluxfor 5 minutes. The reaction mixture was added dropwise to 5N-NaOH 10 mland then extracted with ethyl acetate. The organic layer was washed withwater, dried, and evaporated. The residue was purified by Chromatorex NHsilica gel column chromatography (hexane/ethyl acetate system), wherebythe title compound 98 mg, 70% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.40-1.52 (m, 1H), 1.62 (s, 3H),1.62-1.72 (m, 1H), 2.05-2.22 (m, 2H), 2.36 (t, J=7.4 Hz, 2H), 2.36-2.66(m, 8H), 2.78 (t, J=5.8 Hz, 2H), 4.05 (t, J=5.8 Hz, 2H), 5.13 (s, 1H),5.35 (s, 1H), 6.81-6.85 (m, 2H), 6.93-6.98 (m, 2H), 7.28-7.42 (m, 5H).

The above free compound 98 mg was treated in a usual manner to give thehydrochloride 81 mg of the title compound.

Hydrochloride;

ESI-Mass; 422 (MH+).

Example 83 Synthesis of1-[4-Cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

1-[4-Cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine85 mg obtained in Example 11 was dissolved in dichloromethane 3 ml, and1M-boron tribromide (dichloromethane solution, 0.5 ml) was addeddropwise thereto under ice-cooling. After haeting the mixture underreflux for 5 hours, it was cooled to room temperature and basified withaqueous saturated sodium bicarbonate under ice-cooling. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater, dried over sodium sulfate anhydride, and evaporated. The residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound 30 mg, 36% was obtained as acolorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.16 (d, J=6.6Hz, 3H), 1.19-1.30 (m, 1H), 1.61-1.66 (m, 1H), 1.68-1.71 (m, 1H), 1.80(td, J=4.4 Hz, 13.6 Hz, 1H), 1.99-2.05 (m, 1H), 2.08 (td, J=4.4 Hz, 12.8Hz, 1H), 2.27-2.60 (m, 9H), 2.77 (t, J=5.6 Hz, 2H), 3.71 (m, 1H), 4.03(t, J=5.6 Hz, 2H), 6.64-6.66 (m, 2H), 6.80 (t, J=4.4 Hz, 1H), 6.81 (dd,J=4.4 Hz, 9.2 Hz, 1H), 6.94 (tm, J=8.8 Hz, 2H), 7.13 (m, 1H), 7.15 (m,1H).

ESI-Mass; 440 (MH+).

Oxalic acid (equivalent) was added at room temperature to a solution ofthe above free compound 13 mg in methanol. After the mixture was stirredfor 10 minutes, the solvent was evaporated, whereby the oxalate 16.1 mgof the title compound was obtained. Oxalate; ESI-Mass; 440 (MH+).

Example 84 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-fluorophenoxy)ethyl]piperazine84-1) Ethyl(2-acetyl-4-fluorophenoxy)acetate

5′-Fluoro-2′-hydroxyacetophenone 2.0 g, ethyl iodoacetate 4.16 g andpotassium carbonate 2.7 g were added to acetone 43 ml in a nitrogenatmosphere, and the mixture was stirred overnight under reflux withheating. After cooled to room temperature, the potassium carbonate wasfiltered off through Celite, and the filtrate was partitioned by addingwater and ethyl acetate. The organic layer was washed with water andthen with brine, dried over magnesium sulfate anhydride, and evaporated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound 3.07 g, 99%was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.31 (t, J=7.0 Hz, 3H), 2.72 (s, 3H),4.28 (q, J=7.0 Hz, 3H), 4.70 (s, 2H), 6.81 (dd, J=4.0 Hz, 9.2 Hz, 1H),7.14 (ddd, J=3.2 Hz, 7.2 Hz, 9.2 Hz, 1H), 7.48 (dd, J=3.2 Hz, 8.8 Hz,1H).

84-2) Ethyl (2-Acetoxy-4-fluorophenoxy)acetate

Ethyl (2-acetyl-4-fluorophenoxy) acetate 500 mg, sodium bicarbonate 505mg and methachloroperbenzoic acid 1.80 g were added to dichloromethane10 ml in a nitrogen atmosphere and stirred for 1 day under reflux withheating. The reaction mixture was cooled to room temperature, and 1Maqueous sodium thiosulf ate 5 ml was added thereto and stirred, and themixture was partitioned by adding water and dichloromethane. The organiclayer was washed with water and then with brine, dried over magnesiumsulfate anhydride, and evaporated. The residue was purified by silicagel column chromatography (hexane/ethyl acetate system), whereby thetitle compound 333 mg, 74% was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.30 (t, J=7.1 Hz, 3H), 2.34 (s, 3H),4.26 (q, J=7.1 Hz, 2H), 4.57 (s, 2H), 6.82-6.92 (m, 3H).

84-3) 1-(2-Hydroxy-4-fluorophenoxyacetyl)pyrrolidine

Pyrrolidine 1.87 g was added to ethyl (2-acetoxy-4-fluorophenoxy)acetate and stirred overnight. The reaction solution was partitioned byadding water and ethyl acetate. The organic layer was washed with waterand then with saturated saline, dried over magnesium sulfate anhydride,and evaporated, whereby the title compound (1.20 mg, 96%) was obtainedas a brown oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.82-2.04 (m, 4H), 3.26-3.32 (m, 2H),3.50-3.56 (m, 2H), 4.50 (s, 2H), 6.46 (dt, J=3.1 Hz, 8.9 Hz, 1H), 6.67(dd, J=3.1 Hz, 10.0 Hz, 1H), 6.91 (dd, J=5.5 Hz, 8.9 Hz, 1H).

84-4) 1-(2-Benzyloxy-4-fluorophenoxyacetyl)pyrrolidene

1-(2-Hydroxy-4-fluorophenoxyacetyl) pyrrolidine 82 mg was dissolved inN,N-dimethylformamide 12 ml in a nitrogen atmosphere, and sodium hydride21 mg, 60% oil was added thereto, and the mixture was stirred for 15minutes, and benzyl bromide 89 mg was added thereto, and the mixture wasstirred at room temperature. After 45 minutes, aqueous saturatedammonium chloride was added thereto and stirred, and the mixture waspartitioned by adding water and ethyl acetate. The organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride, and evaporated. The residue was purified by silica gel columnchromatography (diethyl ether) whereby the title compound 100 mg, 97%was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.75-1.90 (m, 4H), 3.48 (t, J=6.8 Hz,4H), 4.63 (s, 2H), 5.09 (s, 2H), 6.58 (ddd, J=2.8 Hz, 8.8 Hz, 11.2 Hz,1H), 6.69 (dd, J=2.8 Hz, 10.0 Hz, 1H), 6.94 (dd, J=5.6 Hz, 8.8 Hz, 1H).

84-5)1-[(4-Cyano-4-methyl-4-phnyl)hexyl]-4-[2-(2-fluorophenoxy)ethyl]piperazine

1-(2-Benzyloxy-4-fluorophenoxyacetyl) pyrrolidine 100 mg was dissolvedin toluene 10 ml in a nitrogen atmosphere, and 3.4Mbis(2-methoxyethoxy)aluminum sodium hydride in toluene (0.09 ml, tradename; Red-Al) was added thereto, and after the mixture was stirred for 1hour, acetone 0.1 ml was added thereto, and the mixture was stirred atroom temperature. After 15 minutes, 1N hydrochloric acid 1 ml was addedthereto and the mixture was stirred, and then partitioned by addingwater and ethyl acetate. The organic layer was washed with water,aqueous saturated sodium bicarbonate and brine in this order, dried overmagnesium sulfate anhydride and evaporated to give an aldehyde 65 mg.This product 65 mg, acetic acid 0.06 ml, and1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 71 mg was dissolved indichloroethane 12.5 ml, and sodium triacetoxyborohydride 107 mg wasadded thereto, and the mixture was stirred at room temperature for 5hours. The reaction mixture was partitioned by adding aqueous saturatedsodium bicarbonate and ethyl acetate. The organic layer was washed withwater and then with brine, dried over magnesium sulfate anhydride, andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound66 mg, 49% was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.10-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.45-1.60 (m, 1H), 1.82-1.93 (m, 1H),2.05-2.20 (m, 2H), 2.20-2.40 (m, 6H), 2.45-2.65 (m, 4H), 2.77 (t, J=5.9Hz, 2H), 4.08 (t, J=5.9 Hz, 2H), 5.06 (s, 2H), 6.57 (brdt, J=3.2 Hz, 8.8Hz, 1H), 6.67 (dd, J=3.2 Hz, 10.0 Hz, 1H), 6.83 (dd, J=5.6 Hz, 8.8 Hz,1H), 7.25-7.45 (m, 10H).

ESI-Mass; 530 (MH+).

84-6)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-fluorophenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzyloxy-4-fluorophenoxy)ethyl]piperazine66 mg and 1,4-cyclohexadiene 0.23 ml were dissolved in ethanol 4 ml, and10% palladium/carbon 6 mg was added thereto, and the mixture was stirredfor 3 hours under reflux with heating. The reaction mixture was filteredthrough Celite and evaporated. The residue was purified by NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the freeform (13 mg, 24%) of the title compound was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.63 (m, 1H), 1.80-1.93 (m, 1H),2.05-2.20 (m, 2H), 2.28-2.35 (m, 2H), 2.35-2.70 (m, 8H), 2.56 (t, J=5.2Hz, 2H), 4.03 (t, J=5.2 Hz, 2H), 6.43 (brdt, J=3.2 Hz, 8.8 Hz, 1H), 6.60(dd, J=3.2 Hz, 10.4 Hz, 1H), 6.91 (dd, J=6.6 Hz, 8.8 Hz,₁H), 7.26-7.33(m, 1H), 7.34-7.39 (m, 4H).

This product 13 mg was treated in a usual manner to give thehydrochloride 11 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.4 Hz, 3H), 1.20-1.35 (m, 1H), 1.58-1.70 (m, 1H), 2.05-2.35 (m, 3H),3.30-3.80 (m, 12H), 4.26 (brs, 2H), 6.50-6.60 (m, 1H), 6.66 (dd, J=3.2Hz, 10.0 Hz, 1H), 6.97 (dd, J=5.8 Hz, 9.0 Hz, 1H), 7.25-7.50 (m, 5H).

ESI-Mass; 440 (MH+).

Example 85 Synthesis of1-[(4-Cyano-4-fluoro-4-phenyl)butyl]-4-[2-fluorophenoxy)ethyl]piperazine85-1) 4-(1,3-Dioxolan-2-yl)-2-fluoro-2-phenylbutyonitrile

4-(1,3-Dioxolan-2-yl)-2-phenylbutyronitrile 1.00 g synthesized accordingto Heterocyclic Chem., 21, 307 (1990) was dissolved in tetrahydrofuran10 ml, and 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran5.52 ml was introduced into it in a nitrogen atmosphere at −78° C. Thetemperature was raised for 30 minutes to −20° C. and then cooled againto −78° C., and a solution of N-fluorobenzene sulfonimide 2.18 g intetrahydrofuran 10 ml was introduced into it. The temperature was raisedfor 1 hour to −30° C., and aqueous saturated ammonium chloride was addedthereto, and the solution was extracted with ethyl acetate and furtherwashed with brine. It was dried over magnesium sulfate anhydride andevaporated. The residue was crystallized from ethanol, the insolubleswere filtered off, and the filtrate was evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound 0.55 g, 51% was obtained.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.86-2.02 (m, 2H), 2.25-2.45 (m, 2H),3.84-4.00 (m, 4H), 4.93 (t, J=4.0 Hz, 1H), 7.40-7.52 (m, 5H).

85-2)1-[(4-Cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

4-(1,3-Dioxolan-2-yl)-2-fluoro-2-phenylbutyronitrile was hydrolyzed withacid to be converted into 2-fluoro-5-oxo-2-phenylpentanenitrile 0.12 g,and this product, alongwith 1-[2-(4-fluorophenyl)ethyl]piperazine 0.14g, was treated in the same manner as in Example 1, whereby the free form(0.14 g, 56%) of the title oily compound was obtained.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.62-1.90 (m, 2H), 2.15-2.35 (m, 2H),2.37 (t, J=7.2 Hz, 2H), 2.45 (bs, 4H), 2.58 (bs, 4H), 2.79 (t, J=6.0 Hz,2H), 4.05 (t, J=6.0 Hz, 2H), 6.80-6.86 (m, 2H), 6.93-7.00 (m, 2H),7.42-7.55 (m, 5H).

This free compound 0.14 g was treated in a usual manner to give thehydrochloride 0.15 g of the title compound.

Hydrochloride; ESI-Mass; 400 (MH+).

Example 86 Synthhesis of1-[(4-Cyano-5-methyl-4-pheny)hexyl]-4-[2-(2-ethoxycarhonylmethoxy-4-fluorophenoxy)ethyl]piperazine8-1) 2-(2-Acetyl-4-fluorophenoxy)ethanol

5′-Fluoro-2′-hydroxyacetophenone 5.0 g, 2-bromoethanol 6.08 g, potassiumcarbonate 13.4 g and sodium iodide 7.28 g were dissolved inN,N-dimethylformamide 108 ml and stirred at 100° C. overnight. Thereaction mixture was cooled and then partitioned by adding water andethyl acetate. The organic layer was washed with water and then withbrine, dried over magnesium sulfate anhydride, and evaporated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system), whereby the title compound 1.66 g, 26% was obtained asa brown oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.36-2.40 (m, 1H), 2.64 (s, 3H),3.96-4.02 (m, 2H), 4.16-4.20 (m, 2H), 6.95 (dd, J=4.0 Hz, 9.2 Hz, 1H),7.16 (ddd, J=3.2 Hz, 7.6 Hz, 9.2 Hz, 1H), 7.43 (dd, J=3.2 Hz, 8.8 Hz,1H).

86-2) 2-(2-Acetoxy-4-fluorophenoxy)ethanol

The title compound compound (96 mg, 68%) was obtained as a colorless oilfrom 2-(2-acetyl-4-fluorophenoxy)ethanol 141 mg, sodium bicarbonate 107mg, and m-chloroperbenzoic acid 379 mg in the same manner as in Example84-2).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.45-2.52 (m, 1H), 2.33 (s, 3H),3.84-3.90 (M, 2H), 4.12-4.16 (m, 2H), 6.80-6.86 (m, 1H), 6.90-6.96 (m,2H).

86-3) 2-(2-Hydroxy-4-fluorophenoxy)ethanol

2-(2-Acetoxy-4-fluorophenoxy)ethanol 1.53 g was dissolved in a mixedsolvent of tetrahydrofuran 10 ml and water 5 ml, then lithium hydroxidemonohydride 294 mg was added thereto, and the mixture was stirred at 90°C. After stirred for 10 hours, the reaction mixture was cooled andpartitioned by adding water and ethyl acetate. The organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride and evaporated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(1.07 g, 80%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.30-2.40 (m, 1H), 3.96-4.02 (M, 2H),4.10-4.14 (m, 2H), 6.51 (ddd, J=3.0 Hz, 8.4 Hz, 8.8 Hz, 1H), 6.69 (dd,J=3.0 Hz, 9.6 Hz, 1H), 6.83 (dd, J=5.2 Hz, 8.8 Hz, 1H), 6.90-6.63 (m,1H).

86-4) 2-(2-Hydroxy-4-fluorophenoxy)ethanol

2-(2-Hydroxy-4-fluorophenoxy)ethanol 245 mg and ethyl bromoacetate 214mg were dissolved in N,N-dimethylformamide 5 ml in a nitrogenatmosphere, and sodium hydride 51 mg, 60% oil was added thereto. Themixture was stirred at 90° C. for 1 hour and then partitioned by addingwater and ethyl acetate. The organic layer was washed with water andthen with brine, dried over magnesium sulfate anhydride, and evaporated.The residue was purified by NH silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound 68 mg, 31% wasobtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.31 (t, J=7.2 Hz, 3H), 3.00-3.10 (m,1H), 3.85-3.92 (m, 2H), 4.10-4.14 (m, 2H), 4.28 (q, J=7.2 Hz, 2H), 4.63(s, 2H), 6.60 (dd, J=2.8 Hz, 9.6 Hz, 1H), 6.64-6.70 (m, 1H), 6.93 (dd,J=5.6 Hz, 9.2 Hz, 1H).

86-5) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2(2-ethoxycarbonylmethoxy-4-fluorophenoxy)ethyl]piperazine

2-(2-Ethoxycarbonylmethoxy-4-fluorophenoxy)ethanol 68 mg andtriethylamine 0.11 ml were dissolved in acetonitrile 5 ml in a nitrogenatmosphere, and methane sulfonyl chloride 36 mg was added thereto. Afterthe mixture was stirred for 1 hour, sodium iodide 47 mg and1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 90 mg in acetonitrile 5ml was added thereto, and the mixture was stirred for 2 hours underreflux with heating. The reaction mixture was partitioned by addingwater and ethyl acetate. The organic layer was washed with water andthen with brine, dried over magnesium sulfate anhydride, and evaporated.The residue was purified by silica gel column chromatography (diethylether), whereby the title compound 82 mg, 59% was obtained as acolorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.27-1.33 (m, 3H), 1.50-1.63 (m, 1H),1.70-1.90 (m, 1H), 2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.60 (m,8H), 2.78 (t, J=6.0 Hz, 2H), 3.15 (s, 2H), 4.10 (t, J=6.0 Hz, 2H),4.55-4.60 (m, 2H), 6.55-6.68 (m, 2H), 6.82-6.92 (m, 1H), 7.26-7.32 (m,1H), 7.32-7.39 (m, 4H).

This product 28 mg was treated in a usual manner to give thehydrochloride 25 mg of the title compound.

Hydrochloride;

ESI-Mass; 526 (MH+).

Example 871-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-fluorophenoxy)ethyl]piperazine

1 M lithium aluminum hydride in tetrahydrofuran 0.38 ml was added to1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-fluorophenoxy)ethyl]piperazine 20 mg in tetrahydrofuran 4 ml in an ice bath in anitrogen atmosphere. After the reaction mixture was stirred for 40minutes, water and 2N aqueous sodium hydroxide were added thereto. Afterthe precipitates were filtered off through Celite, the filtrate wasevaporated. The residue was purified by NH silica gel columnchromatography (ethyl acetate), whereby the title compound 15 mg, 81%was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.45-1.63 (m, 1H), 1.82-1.93 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.35 (m, 2H), 2.40-2.50 (m, 4H), 2.55-2.70 (m,4H), 2.82(t, J=6.0 Hz, 2H), 3.60-3.70 (m, 2H), 4.00-4.20 (m, 4H),6.58-6.67 (m, 1H), 6.68 (dd, J=2.8 Hz, 9.8 Hz, 1H), 6.86 (dd, J=5.6 Hz,8.8 Hz, 1H), 7.26-7.32 (m, 1H), 7.33-7.39 (m, 4H).

This product 15 mg was treated in a usual manner to give thehydrochloride 14 mg of the title compound.

Hydrochloride;

ESI-Mass; 484 (MH+).

Example 88 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-fluorophenoxy)ethyl]piperazine88-1) 1-(2-Methoxy-4-fluorophenoxyacetyl)pyrrolidine

The title compound (90 mg, 69%) was obtained as a colorless crystallinefrom 1-(2-hydroxy-4-fluorophenoxy)acetyl pyrrolidine 123 mg and methyliodide 0.05 ml in the same manner as in Example 84-1).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.80-1.90 (m, 2H), 1.90-2.00 (m, 2H),3.48-3.58 (m, 4H), 3.86(s, 3H), 4.06 (s, 2H), 6.56 (brdt, J=3.2 Hz, 8.8Hz, 1H), 6.64 (dd, J=3.2 Hz, 10.0 Hz, 1H), 6.90 (dd, J=5.6 Hz, 8.8 Hz,1H).

88-2)1-[(4-(Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-fluorophenoxy)ethyl]piperazine

The title compound 39 mg, 24% was obtained as a pale yellow oil from1-(2-methoxy-4-fluorophenoxyacetyl) pyrrolidine 90 mg, 3.4Mbis(2-methoxyethoxy)aluminum sodium hydride in toluene 0.1 ml, and1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.63 (m, 1H), 1.82-1.93 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.35 (m, 2H), 2.30-2.65 (m, 8H), 2.80 (t, J=6.0Hz, 2H), 3.82 (s, 3H), 4.08 (t, J=6.0 Hz, 2H), 6.55 (brdt, J=2.8 Hz, 5.2Hz, 1H), 6.62 (dd, J=2.8 Hz, 10.4 Hz, 1H), 6.81 (dd, J=5.2 Hz, 8.8 Hz,1H), 7.26-7.33 (m, 1H), 7.32-7.39 (m, 4H).

This free compound 39 mg was treated in a usual manner to give thehydrochloride 33 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.68 (d, J=6.6 Hz, 3H), 1.21 (d,J=6.6 Hz, 3H), 1.20-1.32 (m, 1H), 1.58-1.72 (m, 1H), 2.05-2.35 (m, 3H),3.30-3.25 (2H), 3.25-3.70 (m, 10H), 3.78 (s, 3H), 4.33 (brs, 2H), 6.71(brdt, J=3.0 Hz, 8.6 Hz, 1H), 6.95 (dd, J=3.0 Hz, 10.6 Hz, 1H), 6.77(dd, J=5.5 Hz, 8.6 Hz, 1H), 7.34 (m, 1H), 7.42-7.48 (m, 4H).

ESI-Mass; 454 (MH+).

Example 89 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-ispropylanilino)ethyl]piperazine89-1) 2-(N-Isopropylanilino)ethanol

N-isopropyl aniline 1.0 g, ethyl bromoacetate 2.47 g, potassiumcarbonate 5.11 g and sodium iodide 5.55 g were dissolved inN,N-dimethylformamide 14 ml in a nitrogen atmosphere and stirred underreflux with heating. After 1 hour, the reaction mixture was cooled toroom temperature and then partitioned by adding water and diethyl ether,and the organic layer was washed with water and then with brine, driedover magnesium sulfate anhydride, and evaporated. The residue waspurified by silica gel column chromatography (hexane/diethylethersystem) to give N-ethoxycarbonylmethyl-N-isopropyl aniline 1.62 g.A part 550 mg of this product was dissolved in tetrahydrofuran 10 ml,and 1M lithium aluminum hydride in tetrahydrofuran 2.5 ml was addedthereto under cooling in an ice bath in a nitrogen atmosphere. Themixture was stirred in the ice bath for 40 minutes, and water 0.1 ml, 2Naqueous sodium hydroxide 0.1 ml, water 0.3 ml, and diethyl ether 5 mlwere added in this order and stirred. The insolubles were filtered offthrough Celite, and the filtrate was evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound 383 mg, 86% was obtained as acolorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.16 (d, J=6.8 Hz, 6H), 1.84-1.91 (m,1H), 3.32 (t, J=6.0 Hz, 2H), 3.64-3.91 (m, 2H), 3.97 (sept, J=6.8 Hz,1H), 6.78-6.83 (m, 1H), 6.88-6.92 (m, 2H), 7.21-7.27 (m, 2H).

89-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylanilino)ethyl]piperazine

In a nitrogen atmosphere, methane sulfonyl chloride 80 mg was added to asolution of 2-(N-isopropylanilino)ethanol 125 mg and triethylamine 0.24ml in acetonitrile 7 ml. After the mixture was stirred for 1 hour,sodium iodide 157 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg in acetonitrile 3ml were added thereto and stirred for 4 hours under reflux with heating.The reaction solution was partitioned by adding water and ethyl acetate,and the organic layer was washed with water and then with brine, driedover magnesium sulfate anhydride and evaporated. The residue waspurified by NH silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound 80 mg, 25% was obtained as acolorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77(d, J=6.8 Hz, 3H), 1.05-1.15 (m,1H), 1.16 (d, J=6.4 Hz, 6H), 1.20 (d, J=6.4 Hz, 3H), 1.50-1.60 (m, 1H),1.88 (dt, J=4.8 Hz, 13.2 Hz, 1H), 2.07-2.18 (m, 2H), 2.21-2.57 (m, 12H),3.30 (brt, J=8.0 Hz, 2H), 3.99-4.09 (m, 1H), 6.64-6.70 (m, 1H),6.74-6.78 (m, 2H), 7.18-7.23 (m, 2H), 7.27-7.31 (m, 1H), 7.34-7.38 (m,4H).

This free product 80 mg was treated in a usual manner to give thehydrochloride 70 mg of the title compound.

Hydrochloride;

ESI-Mass; 447 (MH+).

Example 90 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylanilino)ethyl]piperazine90-1) 2-(N-cylohexylanilino)ethanol

N-ethoxycarbonylmethyl-N-cyclohexyl aniline 1.89 g was obtained fromN-cyclohexyl aniline 1.30 g in the same manner as in the above example.This product 860 mg was reduced to give the title compound (300 mg,42%).

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.05-1.18 (m, 1H), 1.26-1.44 (m, 4H),1.63-1.71 (m, 1H), 1.80-1.87 (m, 5H), 3.67 (t, J=6.7 Hz, 2H), 3.42 (m,1H), 3.64-3.70 (m, 2H), 6.76-6.81 (m, 1H), 6.86-6.90 (m, 2H), 7.20-7.26(m, 2H).

90-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylanilino)ethyl]piperazine

In a nitrogen atmosphere, methane sulfonyl chloride (80 ml) was added toa solution of 2-(N-cylohexylanilino)ethanol 153 mg and triethylamine0.24 ml in acetonitrile 7 ml. After the mixture was stirred for 1 hour,sodium iodide 157 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg in acetonitrile 3ml were added thereto and stirred at 70° C. overnight. The mixture waspartitioned by adding water and ethyl acetate, and the organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride, and evaporated. The residue was purified by NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound 172 mg, 50% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.03-1.19 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.30-1.45 (m, 3H), 1.48-1.60 (m, 1H),1.64-1.72 (m, 1H), 1.78-1.94 (m, 4H), 2.06-2.20 (m, 2H), 2.20-2.58 (m,12H), 3.34 (brt, J=8.0 Hz, 2H), 3.50-3.56 (m, 1H), 6.61-6.68 (m, 1H),6.71-6.76 (m, 2H), 7.17-7.23 (m, 2H), 7.27-7.31 (m, 1H), 7.34-7.38 (m,4H).

This free compound 172 mg was treated in a usual manner to give thehydrochloride 160 mg of the title compound.

Hydrochloride;

ESI-Mass; 487 (MH+).

Example 91 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(4-isopropylanilino)ethyl]}piperazine91-1) 2-[N-methyl(4-Isopropylanilino)]Ethanol

Methyl chloroformate 1.43 ml was added to a solution of4-isopropylaniline 2.5 g and N,N-diisopropylethylamine 6.45 ml intetrahydrofuran 60 ml in a nitrogen atmosphere. After stirred for 3hours, the reaction solution was partitioned by adding water and ethylacetate. The organic layer was washed with water and then with brine,dried over magnesium sulfate anhydride, and evaporated. The residue wasdissolved in N,N-dimethylformamide 30 ml, and sodium hydride 951 mg, 60%oil was added thereto in a nitrogen atmosphere under cooling in an icebath. After the mixture was stirred in the ice bath for 45 minutes, asolution of ethyl bromoacetate 4.63 g in N,N-dimethylformamide 10 ml wasadded thereto. The reaction mixture was cooled to room temperature,stirred overnight, and partitioned by adding water and ethyl acetate.The organic layer was washed with water and then with brine, dried overmagnesium sulfate anhydride, and evaporated to give residues 5.53 g. Apart 1.5 g of the residues was dissolved in tetrahydrofuran 5 ml andadded dropwise to a previously prepared suspension of lithium aluminumhydride 305 mg in tetrahydrofuran 10 ml in an ice bath in a nitrogenatmosphere. After this addition was finished, the mixture was heated for2 hours under reflux. After the reaction mixture was cooled to roomtemperature, water 0.3 ml, 2N aqueous sodium hydroxide 0.3 ml, water 0.9ml and diethyl ether 15 ml were added thereto in this order understirring. The insolubles were removed by filtration through Celite, andthe filtrate was evaporated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound 900 mg was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.22 (d, J=7.0 Hz, 6H), 1.80-1.90 (m,1H), 2.83 (sept, J=6.8 Hz, 1H), 2.80-2.85 (m, 1H), 2.92 (s, 3H), 3.43(t, J=5.5 Hz, 2H), 3.78-3.84 (m, 2H), 6.78 (d, J=8.6 Hz, 2H), 7.11 (d,J=8.6 Hz, 2H).

91-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(4-isopropylanilino)ethyl]}piperazine

In a nitrogen atmosphere, methane sulfonyl chloride 80 mg was added to asolution of 2-[N-methyl(4-isopropylanilino)]ethanol 135 mg intriethylamine (0.24 ml)/acetonitrile (7 ml). After stirring for about 2hours, sodium iodide 157 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg in acetonitrile 3ml were added thereto and stirred at 70° C. overnight. It waspartitioned by adding water and ethyl acetate. The organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride and evaporated. The residues were purified by silica gelcolumn chromatography (methanol/ethyl acetate system), whereby the titlecompound 78 mg, 48% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.04-1.18 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.21 (d, J=6.9 Hz, 6H), 1.48-1.62 (m, 1H),1.84-1.94 (m, 1H), 2.06-2.20 (m, 2H), 2.22-2.56 (m, 12H), 2.74-2.86 (m,1H), 2.90 (s, 3H), 3.42 (t, J=7.6 Hz, 2H), 6.65 (brd, J=8.7 Hz, 2H),7.08 (brd, J=8.7 Hz, 2H), 7.26-7.32 (m, 1H). 7.33-7.38 (m, 4H).

This free compound 78 mg was treated in a usual manner to give thehydrochloride 70 mg of the title compound.

Hydrochloride;

ESI-Mass; 461 (MH+).

Example 92 Synthesis of 1-[(4-Cyano)-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl (3-Isopropylanilino)ethyl]}piperazine92-1) 2-[N-methyl (3-Isopropylanilino)]ethanol

The title compound 900 mg was obtained from 3-Isopropylaniline 2.5 g inthe same manner as in the above example.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.25 (d, J=6.8 Hz, 6H), 1.78-1.81 (m,1H), 2.80-2.85 (m, 1H), 2.96 (s, 3H), 3.47 (t, J=5.7 Hz, 2H), 3.78-3.84(m, 2H), 6.63-6.99 (m, 4H), 7.18 (brt, J=7.8 Hz, 1H).

92-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(3-Isopropylanilino)ethyl]}piperazine

In a nitrogen atmosphere, methane sulfonyl chloride 80 mg was added to asolution of 2-[N-methyl(3-Isopropylanilino)]ethanol 135 mg andtriethylamine 0.24 ml in acetonitrile 7 ml. After stirring for about 2hours, sodium iodide 157 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg in acetonitrile 3ml were added thereto and stirred at 70° C. overnight. It waspartitioned by adding water and ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by silica gel column chromatography(methanol/ethyl acetate system), whereby the title compound 100 mg, 61%was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.23 (d, J=6.8 Hz, 6H), 1.48-1.62 (m, 1H),1.89 (dt, J=4.4 Hz, 13.6 Hz, 1H), 2.07-2.20 (m, 2H), 2.26-2.32 (m, 2H),2.32-2.57 (m, 10H), 2.78-2.88 (m, 1H), 2.93 (s, 3H), 3.42-3.48 (m, 2H),6.51-6.60 (m, 2H), 7.14 (brt, J=8.0 Hz, 1H), 7.23-7.31 (m, 2H),7.35-7.38 (m, 4H).

This free compound 100 mg was treated in a usual manner to give thehydrochloride 98 mg of the title compound.

Hydrochloride;

ESI-Mass; 461 (MH+).

Example 93 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(2-Isopropylanilino)ethyl]}piperazine93-1) 2-(N-methyl-2-Isopropylanilino)ethanol

The title compound 950 mg was obtained from 2-Isopropylaniline 2.5 g inthe same manner as in the above example.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.22 (d, J=7.0 Hz, 6H), 2.50-2.57 (m,1H), 2.80-2.85 (m, 1H), 2.65 (s, 3H), 3.09 (t, J=5.4 Hz, 2H), 3.51-3.62(m, 1H), 3.62-3.70 (m, 2H), 7.01 (m, 4H), 7.18 (brt, J=7.8 Hz, 1H).

93-2)1-[(4-(Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(2-Isopropylanilino)ethyl]}piperazine

In a nitrogen atmosphere, methane sulfonyl chloride 80 mg was added to asolution of 2-(N-methyl-2-Isopropylanilino) ethanol 135 mg andtriethylamine 0.24 ml in acetonitrile 7 ml. After stirring for about 2hours, the solution was added to sodium iodide 157 mg and1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 100 mg in acetonitrile 3ml, and stirred at 70° C. overnight. It was partitioned by adding waterand ethyl acetate, and the organic layer was washed with water and thenwith brine, dried over magnesium sulfate anhydride, and evaporated. Theresidue was purified by NH silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound 154 mg, 95%was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz,CDCl₃); δ (ppm) 0.76 (d, J=6.4 Hz, 3H), 1.04-1.20 (m,1H), 1.16-1.23 (m, 9H), 1.48-1.60 (m, 1H), 1.87 (dt, J=4.4 Hz, 13.6 Hz,1H), 2.07-2.17 (m, 2H), 2.22-2.48 (m, 12H), 2.65 (s, 3H), 2.99-3.04 (m,1H), 3.46-3.58 (m, 2H), 7.10-7.17 (m, 3H), 7.23-7.31 (m, 2H), 7.34-7.37(m, 4H).

This free compound 154 mg was treated in a usual manner to give thehydrochloride 145 mg of the title compound.

Hydrochloride;

ESI-Mass; 461 (MH+).

Example 94 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine94-1) 2-[3,4-(Methylenedioxy)phenoxy]ethylbromide

Sodium hydroxide 0.15 g was dissolved in water 6 ml, and Sesamol 0.50 gand 1,2-dibromoethane 0.37 ml were added thereto and heated under refluxfor 12 hours. After cooling, water was added thereto, and the productwas extracted with ethyl acetate and further washed with brine. Theproduct was dried over magnesium sulfate anhydride and evaporated. Theresidue was purified by (NH) silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound 0.30 g, 34%was obtained.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 3.59 (t, J=6.4 Hz, 2H), 4.21 (t, J=6.4Hz, 2H), 5.92 (s, 2H), 6.33 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.51 (d, J=2.4Hz, 1H), 6.70 (d, J=8.4 Hz, 1H).

94-2)1-[(4-Cyano)-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine

The free compound 0.12 g, 59% of the title compound was obtained as anoil by treating 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 0.13 gand 2-[3,4-(methylenedioxy)phenoxy]ethylbromide 0.11 g in the samemanner as in Example 59-3).

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (dt, J=4.4 Hz,J=12.4 Hz, 1H), 2.07-2.19 (m, 2H), 2.27 (t, J=7.2 Hz, 2H), 2.36 (bs,4H), 2.54 (bs, 4H), 2.74 (t, J=6.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 5.90(s, 2H), 6.30 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.68(d, J=8.4 Hz, 1H), 7.25-7.33 (m, 1H), 7.35-7.38 (m, 4H).

The above free compound 0.12 g was treated in a usual manner to give thehydrochloride 0.14 g of the title compound.

Hydrochloride;

ESI-Mass; 450 (MH+).

Example 95 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-quinolyloxy)ethyl]piperazine

The free form 0.10 g, 63% of the title compound was obtained as an oilfrom 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine0.12 g and 6-hydroxyquinoline 0.25 g in the same manner as in Example99.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (dt, J=4.4 Hz,J=12.4 Hz, 1H), 2.03-2.20 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.39 (bs,4H), 2.60 (bs, 4H), 2.86 (t, J=6.0 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 7.06(d, J=2.4 Hz, 1H), 7.25-7.40 (m, 7H), 7.99 (d, J=9.2 Hz, 1H), 8.02 (d,J=8.4 Hz, 1H), 8.74-8.78 (m, 1H).

The free compound 0.10 g was treated in a usual manner to give thehydrochloride 0.12 g of the title compound.

Hydrochloride;

ESI-Mass; 457 (MH+).

Example 96 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-isoquinolyloxy)ethyl]piperazine

The free form 0.08 g, 51% of the title compound was obtained as an oilfrom 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine0.12 g and 5-hydroxyquinoline 0.25 g in the same manner as in Example99.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.06-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (dt, J=4.4 Hz,J=12.4 Hz, 1H), 2.04-2.20 (m, 2H), 2.28 (t, J=6.8 Hz, 2H), 2.38 (bs,4H), 2.64 (bs, 4H), 2.95 (t, J=5.6 Hz, 2H), 4.27 (t, J=5.6 Hz, 2H), 6.98(d, J=7.6 Hz, 1H), 7.25-7.33 (m, 1H), 7.33-7.38 (m, 4H), 7.48 (t, J=8.0Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H), 8.52 (d, J=6.0Hz, 1H), 9.20 (s, 1H).

The above free compound 0.08 g was treated in a usual manner to give thehydrochloride 0.10 g of the title compound.

Hydrochloride;

ESI-Mass; 457 (MH+).

Example 97 Synthesis of1-[{2-(5-Cyano-6-methyl-5-phenyl)heptyl}]4-[2-(4-fluorophenoxy)ethyl]piperazine97-1) 4-Cyano-5-methyl-4-phenylhexanoic Acid

2-(1-Methylethyl)-5-oxo-2-phenylpentane nitrile, 6.00 g 27.9 mmol, wasdissolved in a mixed solvent of water 55 ml/t-butyl alcohol 200 ml, andsodium dihydrogen phosphate 4.35 g 27.9 mmol and 2-methyl-2-butene 14.8ml 139 mmol were further added thereto. Sodium chlorite 10.0 g 111 mmolin limited amounts was added thereto and stirred for 2 hours. Thereaction mixture was ice-cooled and acidified by 2N hydrochloric acid.Then, it was extracted with ether, washed with dilute hydrochloric acid,dried over magnesium sulfate, and evaporated. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane system),whereby the title compound, 4.10 g 17.7 mmol, 63.4%, was obtained as awhite solid.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.78 Hz, 3H), 1.23 (d,J=6.59 Hz, 3H), 1.94-2.06 (m, 1H), 2.08-2.23 (m, 2H), 2.38-2.54 (m, 2H),7.29-7.42 (m, 5H).

ESI-MS; 230 (MH−). m.p. 82-84° C.

97-2) N,O-dimethyl-4cyano-5-methyl-4-phenylhexanoic Acid HydroxylamineAmide

4-Cyano-5-methyl-4-phenylhexanoic acid, 2.80 g 12.1 mmol, was dissolvedin tetrahydrofuran 70.0 ml containing a small amount ofN,N-dimethylformamide. Under ice-cooling, oxalyl chloride 1.16 ml wasadded dropwise added thereto and the temperature was raised to roomtemperature. The reaction mixture was evaporated and dissolved again intetrahydrofuran 15.0 ml. Under ice-cooling, previously preparedN,O-dimethyl hydroxylamine hydrochloride 6.00 g was added thereto andthe mixture was added dropwise to a mixed solution of ether and 5Naqueous NaOH. The reaction mixture was washed with brine, dried overmagnesium sulfate, and evaporated. The residue was purified byChromatorex NH silica gel column chromatography (ethyl acetate/hexanesystem), whereby the title compound, 2.72 g 9.90 mmol, 81.9%, wasobtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.80 (d, J=6.78, 3H), 1.23 (d, J=6.78,3H), 1.95-2.08 (m, 1H), 2.08-2.22 (m, 1H), 2.22-2.34 (m, 1H), 2.42-2.63(m, 2H), 3.11 (s, 3H), 3.52 (s, 3H), 7.26-7.42 (m, 5H).

97-3) 5-Cyano-6-methyl-5-phenylhepatan-2-one

The above amide, 140 mg 0.51 mmol, was dissolved in tetrahydrofuran 4.00ml. Under ice-cooling, solution of 1.05 M methyl lithium in ether 0.77ml was added dropwise thereto. The reaction mixture was partitioned byadding aqueous saturated ammonium chloride and ethyl acetate, and theorganic layer was washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 110 mg 0.48mol, 94.1%, was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.78, 3H), 1.22 (d, J=6.59,3H), 2.00-2.23 (m, 6H), 2.37-2.46 (m, 1H), 2.53-2.63 (m, 1H), 7.29-7.42(m, 5H).

97-4)1-[{2-(5-Cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-fluorophenoxy)ethyl]piperazine

110 mg (0.48 mmol) of 5-cyano-6-methyl-5-phenylhepata-2-one, 129 mg 0.58mmol of 1-[2-(4-fluorophenoxy)ethyl]piperazine, and acetic acid 60.0 μlwere dissolved in dichloroethane 3.00 ml. After 5 minutes, sodiumtriacetoxyborohydride 153 mg was added thereto. After 19 hours, thereaction mixture was partitioned by adding aqueous saturated sodiumbicarbonate and ethyl acetate. The organic layer was washed again withaqueous saturated sodium bicarbonate and then with brine, dried overmagnesium sulfate, and evaporated. The residue was purified by silicagel column chromatography (ethyl acetate/methanol system), whereby thetitle compound (20 mg 46 umol, 9.52%) was obtained as a colorless oil.

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.77 (d, J=6.78 Hz, 3H), 0.85-1.16(m, 4H), 1.18-1.23 (m, 3H), 1.28-1.61 (m, 1H), 1.77-1.88 (m, 1H),2.26-2.66 (m, 9H), 2.70-2.80 (m, 2H), 4.00-4.07 (m, 2H), 6.81-6.86 (m,2H), 6.92-6.99 (m, 2H), 7.26-7.33 (m, 1H), 7.33-7.39 (m, 4H).

ESI-MS; 438 (MH+).

Example 98 Synthesis of1-{[4-(7-Cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine98-1) 4-Cyano-5-methyl-5-phenylhexanal

212 mg 0.92 mmol of 4-Cyano-5-methyl-4-phenylhexanol disclosed inExample 2 or 3 of JP 11-70613-A was dissolved in dichloromethane 9 ml.Molecular sieves 4A 100 mg and N-methylmorpholine-N-oxide 162 mg wereadded thereto and stirred. After 13 minutes, tetra-n-propylammoniumperruthenate ((n-C₃H₇)₄NRuO₄, 32.3 mg) was added thereto. After 1 hour,the reaction mixture was evaporated. The residue was purified by silicagel column chromatography (ethyl acetate/hexane system), whereby thetitle compound, (92 mg 0.43 mmol, 46.4%) was obtained as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.80 (d, J=6.78, 3H), 1.24 (d, J=6.59,3H), 2.08-2.24 (m, 3H), 2.43-2.53 (m, 1H), 2.56-2.66 (m, 1H), 7.30-7.43(m, 5H), 9.65 (s, 1H).

98-2) 7-Cyano-8-methyl-7-phenylnonane-4-ol

4-Cyano-5-methyl-5-phenylhexanal, 92 mg 0.43 mmol, 46.4%, was dissolvedin tetrahydrofuran 2 ml. The reaction mixture was ice-cooled, and asolution of 2.0 M propyl magnesium chloride in ether 0.5 ml was addedthereto. The reaction mixture was partitioned by adding aqueoussaturated ammonium chloride and ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate, and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane system), whereby the title compound, 70 mg 0.27 mmol,62.8%, was obtained as a colorless syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.59, 3H), 0.84-0.91 (m,3H), 0.94-1.58 (m, 8H), 1.83-1.92 and 2.34-2.44 (m, total 1H), 2.08-2.19(m, 2H), 3.43-3.62 (m, 1H), 7.27-7.40 (m, 5H).

98-3) 7-Cyano-8-methyl-7-phenylnonane-4-one

7-Cyano-8-methyl-7-phenylnonane-4-ol, 70 mg 0.27 mmol, was dissolved indimethyl sulfoxide 3.00 ml and triethylamine 0.70 ml. A sulfurtrioxide-pyridine complex 64.7 mg was added thereto. After 1 hour, anadditional sulfur trioxide-pyridine complex 80.0 mg was added thereto.The reaction mixture was partitioned by adding aqueous saturated sodiumbicarbonate and ethyl acetate. The organic layer was washed with aqueousammonium chloride and then with brine, dried over magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 50 mg 0.19mmol, 72.0%, was obtained as a colorless syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.78, 3H), 0.83 (t, J=7.42,3H), 1.22 (d, J=6.78,3H), 1.44-1.56 (m, 2H), 1.96-2.06 (m, 1H),2.08-2.33 (m, 4H), 2.36-2.46 (m, 1H), 2.48-2.59 (m, 1H), 7.27-7.42 (m,5H).

98-4)1-{[4-(7-Cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine

50 mg 0.19 mmol of 7-cyano-8-methyl-7-phenylnonane-4-one, 51.1 mg 0.23mmol of 1-[2-(4-fluorophenoxy)ethyl]piperazine, and acetic acid 21.8 μlwere dissolved in dichloroethane 2.00 ml. After 5 minutes, sodiumtriacetoxyborohydride 80.5 mg was added thereto. After 14 hours,additional acetic acid 0.20 ml was added thereto, and after 2 hours,additional dichloroethane 2.00 ml and sodium triacetoxyborohydride 40.0mg were added thereto. After 23 hours, the reaction mixture waspartitioned by adding aqueous saturated sodium bicarbonate and ethylacetate. The organic layer was washed with saturated sodium bicarbonateand then with brine, dried over magnesium sulfate, and evaporated. Theresidue was purified by Chromatorex NH silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 3.00 mg 6.44μmol, 3.39% was obtained as a colorless oil.

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.72-1.60 (m, 14H), 1.80-2.86 (m,15H), 4.06 (t, J=5.86 Hz, H), 6.81-6.87 (m, 2H), 6.93-7.00 (m, 2H),7.28-7.40 (m, 5H).

Example 99 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine99-1) 4-Cyano-5-methyl-4-phenylhexyl Iodide

5.00 g 23.0 mmol of 4-Cyano-5-methyl-4-phenylhexanol disclosed inExample 2 or 3 of JP 11-70613-A was added to and dissolved inacetonitrile 150 ml and triethylamine 3.53 ml. Mesyl chloride, 1.96 ml25.3 mmol, was added thereto. After 25 minutes, sodium iodide 20.7 g wasadded thereto. The reaction mixture was partitioned by adding brine andethyl acetate. The organic layer was washed with aqueous sodiumthiosulfate and then with brine, dried over magnesium sulfate, andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 5. 89 g 18.0mmol, 78.2%, was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.79 (d, J=6.78, 3H), 1.22 (d, J=6.59,3H), 1.37-1.49 (m, 1H), 1.82-1.94 (m, 1H), 1.98-2.26 (m, 3H), 3.04-3.18(m, 2H), 7.28-7.42 (m, 5H).

99-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine

The above iodide, 2.07 g 6.32 mmol, was dissolved in acetonitrile 40 ml.Triethylamine 0.88 ml and 1-ethanol piperazine, 1.07 g 8.22 mmol, wereadded thereto, and the mixture was heated at 50° C. The reaction mixturewas partitioned by adding brine and ethyl acetate. The organic layer waswashed with aqueous 1N-aqueous NaOH and then with brine, dried overmagnesium sulfate, and evaporated. The residue was purified byChromatorex NH silica gel column chromatography (ethyl acetate), wherebythe title compound, 1.92 g 5.83 mmol, 92.2%, was obtained as a paleyellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.78, 3H), 1.06-1.18 (m, 1H)1.20 (d, J=6.59, 3H), 1.49-1.62 (m, 1H), 1.84-1.94 (m, 1H), 2.06-2.62(m, 14H), 3.61 (t, J=5.40, 2H), 7.26-7.40 (m, 5H).

99-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine, 900mg 2.73 mmol, was dissolved in dichloromethane 10 ml. Thionyl chloride0.60 ml was added thereto. The mixture was left for 2 hours, and thenheated under reflux, and 15 minutes thereafter, additional thionylchloride 2.00 ml was added. The reaction solution was poured little bylittle into ice-water, then adjusted to pH 11 with 1N-aqueous NaOH, andpartitioned by adding ethyl acetate. The organic layer was washed withaqueous dilute NaOH and then with brine, dried over magnesium sulfate,and evaporated. The residue was purified by Chromatorex NH silica gelcolumn chromatography (ethyl acetate/hexane system), whereby the titlecompound, 728 mg 2.09 mmol, 76.6%, was obtained as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.59, 3H), 1.06-1.23 (m,1H), 1.20 (d, J=6.59, 3H), 1.48-1.67 (m, 1H), 1.84-1.94 (m, 1H),2.07-2.58 (m, 12H), 2.71 (t, J=7.05, 2H), 3.56 (t, J=7.05, 2H),7.26-7.40 (m, 5H).

99-4)1-[(4-Cyano)-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

4-Hydroxypyridine, 205 mg 2.16 mmol, was suspended in toluene (4 ml),and sodium hydride, 86.4 mg 2.16 mmol, was added thereto. The mixturewas heated at 100° C., and a solution of 150 mg 0.43 mmol of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine intoluene 1 ml was added thereto. After 25 minutes, additional dimethylsulfoxide 2.00 ml was added thereto. After brine was added and thereaction mixture was adjusted to pH 11 with 1N-aqueous NaOH, it waspartitioned by adding ethyl acetate. The organic layer was washed withaqueous dilute NaOH and brine, dried over magnesium sulfate, andevaporated. The residue was purified by Chromatorex NH silica gel columnchromatography (ethyl acetate/hexane system), whereby the titlecompound, 43.0 mg 0.11 mmol, 24.6%, was obtained as a pale yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.78, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.78, 3H), 1.50-1.62 (m, 1H), 1.83-1.93 (m, 1H),2.06-2.65 (m, 12H), 2.80 (t, J=5.86, 2H), 4.12 (t, J=5.86, 2H), 6.78(dd, J=1.65, 4.76, 2H), 7.25-7.39 (m, 5H), 8.41 (dd, J=1.47, 4.76, 2H).

ESI-MS; 407 (MH+).

Example 100 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine

3-Hydroxypyridine, 205 mg 2.16 mmol, was suspended in toluene 2 ml.Sodium hydride, 86.4 mg 2.16 mmol, was added thereto, and the mixturewas heated at 100° C., and then a solution of 150 mg 0.43 mmol of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine intoluene 1 ml was added thereto. After 25 minutes, additional dimethylsulfoxide 1.00 ml was added thereto. After brine was added to thereaction mixture and the mixture was adjusted to pH 11 with 1N-aqueousNaOH, it was partitioned by adding ethyl acetate. The organic layer waswashed with aqueous dilute NaOH and then with brine, dried overmagnesium sulfate, and evaporated. The residue was purified byChromatorex NH silica gel column chromatography (ethyl acetate/hexanesystem), whereby the title compound, 93.0 mg 0.23 mmol, 53.2%, wasobtained as a pale yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.78, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.59, 3H), 1.50-1.63 (m, 1H), 1.82-1.95 (m, 1H),2.06-2.70 (m, 12H), 2.81 (t, J=5.77, 2H), 4.12 (t, J=5.77, 2H), 4.12 (t,J=5.86, 2H), 7.16-7.40 (m, 7H), 8.20-23 (m, 2H), 8.29-8.33 (m, 2H).

ESI-MS; 407 (MH+).

Example 101 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-quinolyloxy)ethyl]piperazine

5-Hydroxyquinoline, 313 mg 2.16 mmol, was dissolved in dimethylsulfoxide 8 ml. Sodium hydride, 86.4 mg 2.16 mmol, was added thereto,and the mixture was heated at 100° C., and then a solution of 150 mg0.43 mmol of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine intoluene 1 ml was added thereto. After brine was added to the reactionmixture and the mixture was adjusted to pH 11 with 1N-aqueous NaOH, itwas partitioned by adding ethyl acetate. The organic layer was washedwith aqueous dilute NaOH and brine, dried over magnesium sulfate, andevaporated. The residue was purified by Chromatorex NH silica gel columnchromatography (ethyl acetate/hexane system), whereby the title compound(77.0 mg 0.11 mmol, 24.6%) was obtained as a pale yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.59, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.59, 3H), 1.50-1.63 (m, 1H), 1.83-1.94 (m, 1H),2.05-2.75 (m, 12H), 2.94 (t, J=5.68, 2H), 4.27 (t, J=5.68, 2H), 6.84 (d,J=7.69, 1H), 7.24-7.40 (m, 5H), 8.41 (dd, J=1.47, 4.76, 2H).

ESI-MS; 457 (MH+).

Example 102 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine, 466mg 1.41 mmol, was dissolved in N,N-dimethylformamide 15 ml. Potassiumt-butoxide, 316 mg 2.82 mmol, was added thereto. After stirring for 5minutes, 4-fluorobenztrifluoride, 0.32 ml 2.54 mmol, was added thereto.After brine was added to the reaction mixture and the mixture wasadjusted to pH 11 with 1N-aqueous NaOH, it was partitioned by addingethyl acetate. The organic layer was washed with aqueous dilute NaOH andbrine, dried over magnesium sulfate, and evaporated. The residue waspurified by Chromatorex NH silica gel column chromatography (ethylacetate/hexane system) whereby the title compound, (432 mg 0.91 mmol,64.7%) was obtained as a colorless syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.78, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.78, 3H), 1.49-1.62 (m, 1H), 1.82-1.93 (m, 1H),2.05-2.65 (m, 12H), 2.80 (t, J=5.86, 2H), 4.11 (t, J=5.86, 2H), 6.95 (d,J=8.42, 2H), 7.26-7.39 (m, 5H), 7.53 (d, J=8.61, 2H).

ESI-MS; 474 (MH+).

Example 103 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine

383 mg 2.66 mmol of 1-naphthol, 438 mg 1.33 mmol of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl) piperazine and420 mg 1.60 mmol of triphenyl phosphine were dissolved intetrahydrofuran 15 ml. Diethyl azodicarboxylate, 0.25 ml 1.60 mmol, wasadded thereto. After brine was added to the reaction mixture and themixture was adjusted to pH 11 with 1N-aqueous NaOH, it was partitionedby adding ethyl acetate. The organic layer was washed with aqueousdilute NaOH and brine, dried over magnesium sulfate, and evaporated. Theresidue was purified by Chromatorex NH silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 123 mg 0.27mmol, 20.3%, was obtained as a colorless syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.78, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.78, 3H), 1.50-1.70 (m, 1H), 1.84-1.95 (m, 1H),2.05-2.75 (m, 12H), 2.96 (t, J=5.68, 2H), 4.28 (t, J=5.68, 2H), 6.79(dd, J=0.92, 6.591H), 7.24-7.52 (m, 9H), 7.76-7.82 (m, 1H), 8.20-8.27(m, 1H).

ESI-MS; 456 (MH+).

Example 104 Synthesis of 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-fluorophenoxy)ethyl]piperazine 104-1)1-Benzyl-4-[2-vinyl-2-(4-fluorophenoxy)ethyl]piperazine

Butadiene monoxide 5.0 g and 1-benzyl piperazine 10.5 g were dissolvedin methylene chloride 60 ml, and ytterbium triflate hydrate 3.7 g wasadded thereto and stirred for 2 hours. Water was added to the reactionmixture which was then extracted with chloroform, dried over sodiumsulfate anhydride, and evaporated to give residue 9.05 g. The residue720 mg, 4-fluorophenoxy 654 mg and triphenyl phosphine 1.53 g weredissolved in tetrahydrofuran 10 ml, and diethyl azodicarboxylate 0.92 mlwas added thereto in an ice bath, and the mixture was stirred overnight.The mixture was partitioned by adding water and ethyl acetate. Theorganic layer was washed with water and brine successively, dried overmagnesium sulfate anhydride, and evaporated. The residue was purified byNH silica gel column chromatography (hexane/ethyl acetate system),whereby the title compound, 919 mg, 92%, w as obtained as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.40-2.50 (m, 4H), 2.50-2.65 (m, 4H),2.60 (dd, J=4.0 Hz, 13.4 Hz, 1H), 2.78 (dd, J=7.5 Hz, 13.4 Hz, 1H), 3.49(s, 2H), 4.48-4.72 (m, 1H), 5.21 (md, J=10.6 Hz, 1H), 5.26 (md, J=17.3Hz, 1H), 5.86 (ddd, J=5.9 Hz, 10.6 Hz, 17.3 Hz, 1H), 6.80-6.88 (m, 2H),6.90-6.97 (m, 2H), 7.20-7.35 (m, 5H).

104-2) 1-Benzyl-4-[2-(4-fluorophenoxy)butyl]piperazine

1-Benzyl-4-[2-vinyl-2-(4-fluorophenoxy)ethyl]piperazine 919 mg wasdissolved in ethanol 20 ml, and palladium hydroxide/carbon 50 mg, 51.5%wet was added thereto, and the mixture was reduced for 8 hours underhydrogen pressure at about 3 kg/cm³. After the insolubles were filteredoff, the filtrate was evaporated, and the residue was purified by NHsilica gel column chromatography (hexane/ethyl acetate system), wherebythe title compound, 717 mg, 77%, was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.95 (t, J=7.5 Hz, 3H), 1.60-1.72 (m,2H), 2.40-2.60 (m, 8H), 2.51 (dd, J=4.6 Hz, 13.3 Hz, 1H), 2.63 (dd,J=6.5 Hz, 13.3 Hz, 1H), 3.49 (s, 2H), 4.18-4.25 (m, 1H), 6.84-6.88 (m,2H), 6.90-6.96 (m, 2H), 7.21-7.29 (m, 1H), 7.29-7.33 (m, 4H).

104-3) 1-[2-(4-Fluorophenoxy)butyl]piperazine

1-Benzyl-4-[2-(4-fluorophenoxy)butyl]piperazine 717 mg was dissolved indichloroethane 10 ml, and 1-chloroethyl chloroformate 598 mg was addedthereto, and the mixture was stirred for 2 hours under reflux withheating. After the reaction mixture was concentrated, methanol 10 ml wasadded thereto, and the mixture was stirred for 1 hour under reflux withheating. After the mixture was evaporated, it was partitioned by addingether and 2N hydrochloric acid, and the aqueous layer was neutralizedwith 2N sodium hydroxide followed by extracting with ethyl acetate. Theorganic layer was washed with water and brine successively, dried overmagnesium sulfate anhydride and evaporated, whereby the title compound168 mg, 32% was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.96 (t, J=7.5 Hz, 3H), 1.60-1.80 (m,2H), 2.40-2.50 (m, 4H), 2.49 (dd, J=4.4 Hz, 13.4 Hz, 1H), 2.63 (dd,J=6.6 Hz, 13.4 Hz, 1H), 2.83-2.90 (m, 4H), 4.20-4.28 (m, 1H), 6.85-6.90(m, 2H), 6.91-6.97 (m, 2H).

104-4)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)butyl]piperazine

In a nitrogen atmosphere,2-[1-methyl(ethyl)]-2-phenyl-5-hydroxypentanenitrile 142 mg andtriethylamine 0.27 ml were dissolved in acetonitrile 10 ml, and methanesulfonyl chloride 0.06 ml was added thereto. After the mixture wasstirred for 1 hour, sodium iodide 490 mg and a solution of1-[2-ethyl-2-(4-fluorophenoxy)ethyl]piperazine 165 mg in acetonitrile 5ml were added thereto and stirred at 70° C. overnight. The reactionmixture was partitioned by adding water and ethyl acetate. The organiclayer was washed with water and brine successively, dried over magnesiumsulfate anhydride and evaporated. The residue was purified by NH silicagel column chromatography (hexane/ethyl acetate system), whereby thetitle compound 130 mg, 44% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.76 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.5Hz, 3H), 1.05-1.15 (m, 1H), 1.19 (d, J=6.4 Hz, 3H), 1.55-1.75 (m, 2H),1.87 (dt, J=4.2 Hz, 13.2 Hz, 1H), 2.05-2.18 (m, 2H), 2.20-2.37 (m, 6H),2.40-2.50 (m, 5H), 2.61 (dd, J=6.4 Hz, 13.6 Hz, 1H), 4.15-4.22 (m, 1H),6.82-6.88 (m, 2H), 6.91-6.97 (m, 2H), 7.23-7.30 (m, 1H), 7.30-7.38 (m,4H).

This free compound 130 mg was treated in a usual manner to give thehydrochloride 135 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H) 0.86 (t, J=7.4Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 1.20-1.35 (m, 2H), 1.55-1.70 (m, 3H),2.05-2.25 (m, 3H), 3.00-4.00 (m, 11H), 4.75-4.90 (m, 1H), 7.05-7.12 (m,2H), 7.12-7.17 (m, 2H), 7.35-7.40 (m, 1H), 7.50-7.70 (m, 4H).

ESI-Mass; 452 (MH+).

Example 105 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-quinazolinyloxy)ethyl]piperazine

The free form 0.059 g, 45% of the title oily compound was obtained from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine 0.10 gand 4-hydroxyquinazoline 0.21 g in the same manner as in Example 99.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.04-1.18 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.47-1.60 (m, 1H), 1.88 (dt, J=4.4 Hz,J=12.4 Hz, 1H), 2.04-2.18 (m, 2H), 2.25 (t, J=7.6 Hz, 2H), 2.31 (bs,4H), 2.49 (bs, 4H), 2.69 (t, J=6.0 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H),7.25-7.32 (m, 1H), 7.32-7.38 (m, 4H), 7.47-7.53 (m, 1H), 7.68-7.78 (m,1H), 8.04 (s, 1H), 8.29-8.32 (m, 1H).

The above free compound 0.059 g was treated in a usual manner to givethe hydrochloride 0.05 g of the title compound.

Hydrochloride;

ESI-Mass; 458 (MH+).

Example 106 Synthesis of1-[(4-Cyano-9-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine106-1) 2-[4-(3-Pyridyl)phenoxy]ethanol

In a nitrogen atmosphere, 2-(4-bromophenoxy)ethanol 500 mg, diethyl(3-pyridyl) borane 509 mg, finely pulverized potassium hydroxide 388 mg,tetra-n-butyl ammonium bromide 74 mg and a tetrakis-triphenyl phosphinepalladium complex 133 mg were added to tetrahydrofuran 10 ml and stirredunder reflux with heating. After stirring for 2 hours, the mixture wascooled to room temperature and partitioned by adding water and ethylacetate. The organic layer was washed with water and then with brine,dried over magnesium sulfate anhydride, and evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (233 mg, 50%) was obtained as a paleyellow crystalline.

¹H-NMR (400 MHz, CDCl₃) δ (ppm) 2.45 (t, J=6.2 Hz, 1H), 3.97-4.02 (m,2H) 4.12-4.17 (m, 2H), 7.02 (brd, J=8.8 Hz, 2H), 7.32-7.36 (m, 1H), 7.51(brd, J=8.8 Hz, 2H), 7.80-7.85 (m, 1H), 8.53-8.56 (m, 1H), 8.78-8.82 (m,1H).

ESI-Mass; 216 (MH+).

106-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine

In a nitrogen atmosphere, 2-[4-(3-pyridyl)phenoxy]ethanol 68 mg andtriethylamine 0.13 ml were dissolved in acetonitrile 6 ml in an icebath, and methane sulfonyl chloride 40 mg was added thereto. Afterstirring for 3 hours, sodium iodide 142 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 90 mg in acetonitrile 3ml were added thereto, and the mixture was stirred for 5 hours underreflux with heating. After cooling, the reaction solution waspartitioned by adding water and ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound17 mg, 11% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.50-2.65 (m,4H), 2.82 (t, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 2H), 7.00 (d, J=8.8 Hz,2H), 7.20-7.40 (m, 6H), 7.50 (d, J=8.8 Hz, 2H), 7.80-7.84 (m, 1H),8.50-8.55 (m, 1H), 8.80-8.81 (m, 1H).

This free compound 17 mg was treated in a usual manner to give thehydrochloride 13 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.70 (m, 1H), 2.05-2.30 (m, 3H),3.00-3.25 (m, 2H), 3.25-3.80 (m, 10H), 4.45-4.50 (m, 2H), 7.19 (d, J=8.8Hz, 2H), 7.33-7.40 (m, 1H), 7.40-7.50 (m, 4H), 7.86 (d, J=8.8 Hz, 2H),7.96 (dd, J=5.5 Hz, 8.1 Hz, 1H), 8.68 (brd, J=8.1 Hz, 1H), 8.77 (dd,J=1.1 Hz, 5.5 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H).

ESI-Mass; 483 (MH+).

Example 107 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine107-1) 2-[3-(3-Pyridyl)phenoxy]ethanol

The title compound 435 mg, 88% was obtained as a pale yellow crystallinefrom 2-(3-bromophenoxy)ethanol 500 mg in the same manner as in the aboveexample.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.13 (t, J=6.2 Hz, 1H), 3.98-4.04 (m,2H), 4.14-4.20 (m, 2H), 6.95-7.00 (m, 1H), 7.12-7.15 (m, 1H), 7.17-7.22(m, 1H), 7.34-7.44 (m, 2H), 7.84-7.90 (m, 1H), 8.58-8.62 (m, 1H),8.82-8.86 (m, 1H).

ESI-Mass; 216 (MH+).

107-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine

In a nitrogen atmosphere, 2-[3-(3-pyridyl)phenoxy]ethanol 68 mg andtriethylamine 0.13 ml were dissolved in acetonitrile 6 ml in an icebath, and methane sulfonyl chloride 40 mg was added thereto. Afterstirring for 3 hours, sodium iodide 142 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 90 mg in acetonitrile 3ml were added thereto, and the mixture was stirred for 5 hours underreflux with heating. After cooling, the reaction mixture was partitionedby adding water and ethyl acetate. The organic layer was washed withwater and brine, dried over magnesium sulfate anhydride, and evaporated.The residue was purified by NH silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound (44 mg, 29%)was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.45-2.65 (m,4H), 2.82 (t, J=5.9 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 6.91-6.98 (m, 1H),7.10-7.12 (m, 1H), 7.14-7.18 (m, 1H), 7.25-7.32 (m, 1H), 7.32-7.40 (m,6H), 7.83-7.87 (m, 1H), 8.56 (dd, J=1.5 Hz, 4.8 Hz, 1H), 8.23 (dd, J=0.7Hz, 2.4 Hz, 1H).

This free compound 29 mg was treated in a usual manner to give thehydrochloride 23 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.35 (m, 1H), 1.58-1.73 (m, 1H), 2.05-2.25 (m, 3H),3.00-3.85 (m, 12H), 4.50-4.56 (m, 2H), 7.13-7.18 (m, 1H), 7.33-7.40 (m,1H), 7.42-7.54 (m, 7H), 7.97 (dd, J=5.5 Hz, 8.2 Hz, 1H), 8.70 (brd,J=8.2 Hz, 1H), 8.82 (dd, J=1.3 Hz, 5.5 Hz, 1H), 9.20 (d, J=1.8 Hz, 1H).

ESI-Mass; 483 (MH+).

Example 108 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine108-1) 2-(4-Bromophenoxy)ethanol

In a nitrogen atmosphere, 4-bromophenol 5.0 g, 2-bromoethanol 5.42 g,and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30ml, and the mixture was stirred at 100° C. After 1 hour, the mixture wascooled to room temperature and partitioned by adding water and diethylether. The organic layer was washed with water and brine, dried overmagnesium sulfate anhydride and evaporated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate system), wherebythe title compound 5.15 g, 82% was obtained as a colorless crystalline.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.95-2.00 (m, 1H), 3.94-3.99 (m, 2H),4.04-4.07 (m, 2H), 6.81 (brd, J=9.2 Hz, 2H), 7.38 (brd, J=9.2 Hz, 2H).

108-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

In a nitrogen atmosphere, 2-(4-bromophenoxy)ethanol 350 mg andtriethylamine 0.68 ml were dissolved in acetonitrile 16 ml, and methanesulfonyl chloride 221 mg was added thereto. After stirring for 1 hour,sodium iodide 725 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 460 mg in acetonitrile 8ml were added thereto, and the mixture was stirred for 3 hours underreflux with heating. After cooling, the reaction mixture was partitionedby adding water and ethyl acetate, and the organic layer was washed withwater and brine. It was dried over magnesium sulfate anhydride andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound587 mg, 75% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.43 (m, 4H), 2.43-2.60 (m,4H), 2.77 (t, J=5.9 Hz, 2H), 4.04 (t, J=5.9 Hz, 2H), 6.77 (d, J=8.8 Hz,2H), 7.25-7.32 (m, 1H), 7.32-7.38 (m, 6H).

This free compound 55 mg was treated in a usual manner to give thehydrochloride 50 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.70 (m, 1H), 2.05-2.30 (m, 3H),3.00-3.80 (m, 12H), 4.34 (brs, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.33-7.40(m, 1H), 7.42-7.46 (m, 4H), 7.48 (d, J=8.8 Hz, 2H).

ESI-Mass; 484 (M[₇₉Br]H+), 486 (M[₈₁Br]H+).

Example 109 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine109-1) 2-(3-Bromophenoxy)ethanol

In a nitrogen atmosphere, 3-bromophenol 5.0 g, 2-bromoethanol 5.42 g,and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30ml, and the mixture was stirred at 100° C. After 1 hour, the reactionmixture was cooled to room temperature and partitioned by adding waterand diethyl ether. The organic layer was washed with water and then withbrine, dried over magnesium sulfate anhydride and evaporated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate system), whereby the title compound (4.85 g, 77%) was obtainedas a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.95-2.00 (m, 1H), 3.94-3.99 (m, 2H),4.04-4.09 (m, 2H), 6.84-6.88 (m, 1H), 7.07-7.17 (m, 3H).

109-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

In a nitrogen atmosphere, 2-(3-bromophenoxy)ethanol 350 mg andtriethylamine 0.68 ml were dissolved in acetonitrile 16 ml, and methanesulfonyl chloride 221 mg was added thereto. After the mixture wasstirred for 1 hour, sodium iodide 725 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 460 mg in acetonitrile 8ml were added thereto, and the mixture was stirred for 3 hours underreflux with heating. After cooling, the reaction mixture was partitionedby adding water and ethyl acetate. The organic layer was washed withwater and then with brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(659 mg, 84%) was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.10-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.83-1.95 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.45-2.65 (m,4H), 2.77 (t, J=5.9 Hz, 2H), 4.05 (t, J=5.9 Hz, 2H), 6.80-6.84 (m, 1H),7.04-7.18 (m, 3H), 7.26-7.32 (m, 1H), 7.35-7.38 (m, 4H).

This free product 71 mg was treated in a usual manner to give thehydrochloride 60 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 1.11 (d,J=6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.70 (m, 1H), 2.05-2.30 (m, 3H),3.00-3.80 (m, 12H), 4.38 (brs, 2H), 6.98-7.04 (m, 1H), 7.15-7.30 (m,3H), 7.33-7.40 (m, 1H), 7.42-7.50 (m, 4H).

ESI-Mass; 484 (M[₇₉Br]H+), 486 (M[₈₁Br]H+).

Example 110 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine110-1) 2-(2-Bromophenoxy)ethanol

In a nitrogen atmosphere, 2-bromophenol 5.0 g, 2-bromoethanol 5.42 g,and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30ml, and the mixture was stirred at 100° C. After about 2.5 hours, thereaction mixture was cooled to room temperature and partitioned byadding water and diethyl ether. The organic layer was washed with waterand then with brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by silica gel column chromatography(hexane/ethyl acetate system), whereby the title compound 5.09 g, 81%was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.25 (t, J=6.6 Hz, 1H), 3.96-4.03 (m,4H), 4.12-4.18 (m, 4H), 6.89 (ddd, J=1.5 Hz, 7.5 Hz, 7.9 Hz, 1H), 6.93(dd, J=I.5 Hz, 8.2 Hz, 1H), 7.27 (ddd, J=1.7 Hz, 7.5 Hz, 8.2 Hz, 1H),7.55 (dd, J=1.7 Hz, 7.9 Hz, 1H).

110-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine

In a nitrogen atmosphere, 2-(2-bromophenoxy)ethanol 350 mg andtriethylamine 0.68 ml were dissolved in acetonitrile 16 ml, and methanesulfonyl chloride 221 mg was added thereto. After the mixture wasstirred for 1 hour, sodium iodide 725 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 460 mg in acetonitrile 8ml were added thereto, and the mixture was stirred for 3 hours underreflux with heating. After cooling, the reaction mixture was partitionedby adding water and ethyl acetate, and the organic layer was washed withwater and then with brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound470 mg, 60% was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.80-1.95 (m, 1H),2.05-2.20 (m, 2H), 2.23-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.50-2.70 (m,4H), 2.86 (t, J=5.8 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 6.80-6.90 (m, 2H),7.21-7.32 (m, 2H), 7.33-7.38 (m, 4H), 7.52 (dd, J=1.5 Hz, 7.9 Hz, 1H).

This free product 61 mg was treated in a usual manner to give thehydrochloride 50 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.8 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.20-1.35 (m, 1H), 1.58-1.70 (m, 1H), 2.05-2.35 (m, 3H),3.00-3.85 (m, 12H), 4.67 (brs, 2H), 6.92-6.98 (m, 1H), 7.14-7.18 (m,1H), 7.34-7.40 (m, 2H), 7.42-7.48 (m, 4H), 7.60 (dd, J=1.6 Hz, 8.0 Hz,1H).

ESI-Mass; 484 (M[₇₉Br]H+), 486 (M[₈₁Br]H+).

Example 111 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine

The free compound 0.05 g, 34% of the title compound was obtained as anoil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine 0.11 gand 4-(imidazole-1-yl) phenol 0.25 g in the same manner as in Example99.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.78 (d, J=6.8 Hz, 3H), 1.06-1.20 (m,1H), 1.21 (d, J=6.8 Hz, 3H), 1.50-1.63 (m,₁H), 1.89 (dt, J=4.4 Hz,J=12.4 Hz, 1H), 2.05-2.20 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 2.38 (bs,4H), 2.57 (bs, 4H), 2.81 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 6.98(d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.26-7.33 (m, 3H), 7.33-7.40(m, 4H), 7.75 (s, 1H).

The above free compound 0.05 g was treated in a usual manner to give thehydrochloride 0.052 g of the title compound.

Hydrochloride;

ESI-Mass; 472 (MH+).

Example 112 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinyloxy)ethyl]piperazine

The free compound 0.03 g, 26% of the title compound was obtained as anoil from1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine (0.10g) and 2-hydroxypyrimidine 0.19 g in the same manner as in Example 99.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.18 (m,1H), 1.19 (d, J=6.8 Hz, 3H), 1.48-1.60 (m, 1H), 1.89 (dt, J=4.4 Hz,J=12.0 Hz, 1H), 2.07-2.37 (m, 8H), 2.46 (bs, 4H), 2.70 (t, J=6.0 Hz,2H), 3.96 (t, J=6.0 Hz, 2H), 6.26 (dd, J=4.0 Hz, J=6.4 Hz, 1H),7.26-7.33 (m, 1H), 7.33-7.49 (m, 4H), 7.66 (dd, J=2.8 Hz, J=6.4 Hz, 1H),8.56 (dd, J=2.8 Hz, J=4.0 Hz, 1H).

The above free compound 0.03 g was treated in a usual manner to give thehydrochloride 0.03 g of the title compound.

Hydrochloride;

ESI-Mass; 408 (MH+).

Example 113 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(3-pyridyl)phenoxy]ethyl}piperazine113-1) 2-[2-(3-Pyridyl)phenoxy]ethanol

The title compound 111 mg, 22% was obtained as a pale yellow crystallinefrom 2-(2-bromophenoxy)ethanol 500 mg in the same manner as in the aboveexample.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 3.89 (brt, J=4.4 Hz, 2H), 4.11 (brt,J=4.4 Hz, 2H), 7.03 (brd, J=8.6 Hz, 1H), 7.06-7.12 (m, 1H), 7.30-7.40(m, 3H), 7.86 (brd, J=7.9 Hz, 1H), 8.40-8.60 (m, 1H), 8.65-8.90 (m, 1H).

ESI-Mass 216 (MH+).

113-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

In a nitrogen atmosphere, 2-[2-(3-pyridyl)phenoxy]ethanol 80 mg andtriethylamine 0.13 ml were dissolved in acetonitrile 6 ml in an icebath, and methane sulfonyl chloride 40 mg was added thereto. Afterstirring the mixture for 3hours, sodium iodide 142 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 90 mg in acetonitrile 3ml were added thereto and stirred for 5 hours under reflux conditions.After cooling, the reaction solution was partitioned by adding water andethyl acetate. The organic layer was washed with water and then withbrine, dried over magnesium sulfate anhydride and evaporated. Theresidue was purified by silica gel column chromatography (methanol/ethylacetate system), whereby the title compound (46 mg, 26%) was obtained asa pale yellow oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.9 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.30-2.40 (m, 6H), 2.40-2.55 (m, 4H), 2.71 (t, J=5.9Hz, 2H), 4.09 (t, J=5.9 Hz, 2H), 6.98 (brd, J=8.1 Hz), 7.02-7.08 (m,1H), 7.25-7.38 (m, 8H), 7.86-7.92 (m, 1H), 8.53 (dd, J=1.6 Hz, 4.9 Hz,1H), 8.76 (dd, J=0.7 Hz, 2.2 Hz, 1H).

This free compound 46 mg was treated in a usual manner to give thehydrochloride 30 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.6 Hz, 3H), 1.10 (d,J=6.6 Hz, 3H), 1.20-1.35 (m, 1H), 1.55-1.70 (m, 1H), 2.05-2.25 (m, 3H),3.00-3.85 (m, 12H), 4.43-4.50 (m, 2H), 7.15-7.22 (m, 1H), 7.34-7.40 (m,1H), 7.42-748 (m, 4H), 7.50-7.56 (m, 2H), 8.00-8.08 (m, 1H), 8.66-8.74(m, 1H), 8.78-8.84 (m, 1H), 9.14 (brs, 1H).

ESI-Mass; 483 (MH+).

Example 114 Synthesis of1-[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine114-1) 3-Methyl-2-(2-thienyl)butane Nitrile

2-Thienyl acetonitrile, 15 g 0.12 mol, was dissolved in tetrahydrofuran125 ml and added dropwise to a suspension of sodium amide 4.75 g 0.12mol in tetrahydrofuran 250 ml under ice-cooling. After stirring for 5minutes, a solution of 2-bromopropane 11.4 ml 0.12 mol intetrahydrofuran 125 ml was added dropwise thereto. Aqueous saturatedammonium chloride was added to the reaction mixture which was thenextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate and evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane system), wherebythe title compound, 5.56 g 33.6 mmol, 28.0% was obtained as a yellowoil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.08 (d, J=6.80 Hz, 3H), 1.12 (d,J=6.80 Hz, 3H), 2.14-2.24 (m, 1H), 3.95 (d, J=6.00 Hz, 1H), 6.99 (dd,J=4.00 Hz, 5.20 Hz, 1H), 7.05-7.08 (m, 1H), 7.27 (dd, J=1.20 Hz, 5.20Hz, 1H).

114-2) Ethyl 4-Cyano-5-methyl-4-(2-thienyl)hexanoate

3-Methyl-2-(2-thienyl)butane nitrile 5.56 g 33.6 mmol and ethyl acrylate4.00 ml 37.0 mmol were dissolved in tetrahydrofuran 100 ml. Potassiumt-butoxide, 566 mg 5.04 mmol, was added little by little thereto at roomtemperature. Generation of heat continued during this step. Afterstirring for 1 hour, brine 100 ml and aqueous saturated ammoniumchloride 150 ml were added thereto successively, and the mixture wasextracted with ether 1 L. The organic layer was washed with brine 500 mland water 500 ml successively, dried over magnesium sulfate anhydrideand evaporated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane system), whereby the title compound(5.57 g 21.0 mmol, 62.5%) was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.92 (d, J=6.78 Hz, 3H), 1.22 (d,J=7.14 Hz, 3H), 1.23 (t, J=7.14, 3H), 2.01-2.19 (m, 3H), 2.41-2.58 (m,2H), 4.01-4.15 (m, 2H), 6.96 (dd, J=3.60 Hz, 5.13 Hz1H), 7.12 (dd,J=1.20 Hz, 3.60 Hz, 1H), 7.29 (dd, J=1.20 Hz, 5.13 Hz, 1H).

114-3) 4-Cyano-5-methyl-4-(2-thienyl)hexanol

The above ester, 5.50 g 20.7 mmol, was dissolved in tetrahydrofuran 100ml and cooled to −30 to −40° C. A solution of 1 M lithium aluminumhydride in tetrahydrofuran 150 ml was added dropwise thereto and thetemperature was raised for 1 hour to 0° C. The reaction mixture wascooled again, and water 0.60 ml, 5 N aqueous sodium hydroxide 0.60 mland water 1.80 ml were added thereto successively, and the mixture wasfiltered through Celite and evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane system), wherebythe title compound, 3.99 g 17.9 mmol, 86.3%, was obtained as a yellowoil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.92 (d, J=6.78 Hz, 3H), 1.19 (d,J=6.78 Hz, 3H), 1.33-1.46 (m, 1H), 1.65-1.77 (m, 1H), 1.80-1.90 (m, 1H),2.08 (sept, J=6.78 Hz, 1H), 2.27 (ddd, J=4.40 Hz, 12.0 Hz, 13.2 Hz, 1H),3.63 (brd-s, 2H), 6.96 (dd, J=3.60 Hz, 5.20 Hz, 1H), 7.11-7.14 (m, 1H),7.27 (dd, J=1.20 Hz, 5.20 Hz, 1H).

114-4) [4-Cyano-5-methyl-4-(2-thienyl)hexyloxy]-t-butyldimethyl Silane

(wherein TBS represents t-butyldimethylsilyl group)

4-Cyano-5-methyl-4-(2-thienyl)hexanol, 2.00 g 8.95 mmol, was dissolvedin N,N-dimethylformamide 50 ml. At room temperature, imidazole 1.83 g26.9 mmol and t-butyl dimethyl chlorosilane 1.55 g 10.3 mmol were addedthereto successively. Brine was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate anhydride and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane system), whereby the title compound (2.83 g 8.95 mmol,100%) was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.01 (s, 3H), 0.02 (s, 3H), 0.88 (s,9H), 0.92 (d, J=6.78 Hz, 3H), 1.18 (d, J=6.78 Hz, 3H), 1.27-1.41 (m,1H), 1.59-1.71 (m, 1H) 1.83 (ddd, J=4.40 Hz, 12.4 Hz, 13.2 Hz, 1H), 2.07(sept, J=6.78 Hz, 1H), 2.22 (ddd, J=4.40 Hz, 12.4 Hz, 13.2 Hz, 1H), 3.59(t, J=6.04 Hz, 2H), 6.95 (dd, J=3.60 Hz, 5.20 Hz, 1H), 7.11 (dd, J=1.20Hz, 3.60 Hz, 1H), 7.26 (dd, 1.20 Hz, 5.20 Hz, 1H).

114-5) [4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-t-butyldimethylSilane

[4-Cyano-5-methyl-4-(2-thienyl)hexyloxy]-t-butyldimethyl silane, 2.72 g8.95 mmol, was dissolved in N,N-dimethylformamide 7 ml.N-bromosucciimide 1.75 g 9.83 mmol was added thereto at room temperatureand heated at 80° C. Brine was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate anhydride and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane system), whereby the title compound, 2.56 g 6.15 mmol,68.7%, was obtained as a colorless oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s,9H), 0.94 (d, J=6.78 Hz, 3H), 1.17 (d, J=6.59 Hz, 3H), 1.32-1.44 (m,1H), 1.59-1.80 (m, 2H), 1.95-2.06 (m, 1H), 2.15-2.25 (m, 1H), 3.60 (t,J=5.86 Hz, 2H), 6.88 (d, J=3.60 Hz, 1H), 6.91 (d, J=3.60 Hz, 1H).

114-6) [4-Cyano-5-methyl-4-(2-formyl-5-thienyl)hexyloxy]-t-butyldimethylSilane

A solution of[4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-t-butyldimethyl silane,1.42 g 3.41 mmol, in tetrahydrofuran 20 ml was cooled to −70° C. Asolution of 1.53 M butyl lithium in hexane 1.52 ml was added dropwisethereto and stirred for 10 minutes. N,N-dimethylformamide 1.52 ml wasadded thereto, and the temperature was raised to room temperature.Aqueous saturated ammonium chloride and brine were added to the reactionmixture which was then extracted with ether. The organic layer waswashed with brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 515 mg 1.41mmol, 41.3%, was obtained as a yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.01 (s, 3H), 0.02 (s, 3H), 0.87 (s,9H), 0.93 (d, J=6.59 Hz, 3H), 1.21 (d, J=6.59 Hz, 3H), 1.22-1.36 (m,1H), 1.60-1.73 (m, 1H), 1.80-1.90 (m, 1H), 2.11 (sept, J=6.59 Hz, 1H),2.24-2.34 (m, 1H), 3.59 (t, J=5.86 Hz, 2H), 7.26 (d, J=3.60 Hz, 1H),7.65 (d, J=3.60 Hz, 1H), 9.89 (s, 1H).

114-7) [4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyloxy]-t-butyldimethylSilane

[4-Cyano-5-methyl-4-(2-formyl-5-thienyl)hexyloxy]-t-butyldimethylsilane, 510 mg 1.39 mmol, was dissolved in ethanol 5 ml, and a solutionof hydroxylamine hydrochloride 145 mg 2.09 mmol and sodium acetate 228mg 2.78 mmol in water 1.25 ml was added thereto, and the mixture washeated at 80° C. Brine was added to the reaction mixture and thenextracted with ether. The organic layer was washed with brine, driedover magnesium sulfate anhydride, and evaporated to give an oximecompound. This oxime compound was dissolved in N,N-dimethylformamide 10ml and cooled at 0° C., followed by adding carbodiimidazole. Thereafter,the mixture was heated at 60° C., and 20 minutes later, triethylaminewas added thereto. Under cooling, brine was added to the reactionmixture which was then extracted with ether. The organic layer waswashed with brine, dried over magnesium sulfate anhydride, andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane system), whereby the title compound, 452 mg 1.25mmol, 89.9%, was obtained as a yellow oil.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s,9H), 0.93 (d, J=6.59 Hz, 3H), 1.20 (d, J=6.59 Hz, 3H), 1.23-1.36 (m,1H), 1.60-1.73 (m, 1H), 1.80-1.90 (m, 1H), 2.08 (sept, J=6.59 Hz, 1H),2.22-2.32 (m, 1H), 3.60 (t, J=5.60 Hz, 2H), 7.14 (d, J=3.60 Hz, 1H),7.51 (d, J=3.60 Hz, 1H).

114-8) 4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexanol

[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyloxy]-t-butyldimethylsilane,452 mg 1.25 mmol, was dissolved in 10 ml tetrahydrofuran and cooled at0° C. A solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran1.38 ml was added dropwise thereto, and then the temperature was raisedto room temperature. Aqueous saturated ammonium chloride and brine wereadded to the reaction mixture which was then extracted with ether. Theorganic layer was washed with brine, dried over magnesium sulfateanhydride, and evaporated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane system), whereby the titlecompound, 273 mg 1.10 mmol, 87.9%, was obtained as a yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.94 (d, J=6.59 Hz, 3H), 1.22 (d,J=6.78 Hz, 3H), 1.28-1.42 (m, 1H), 1.66-1.78 (m, 1H), 1.83-1.93 (m, 1H),2.03-2.16 (m, 1H), 2.32 (ddd, J=4.40 Hz, 12.4 Hz, 13.2 Hz, 1H),3.58-3.74 (m, 2H), 7.16 (d, J=3.60 Hz, 1H), 7.52 (d, J=3.60 Hz, 1H).

114-9)1-[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexanol, 273 mg 1.10 mmol, wasdissolved in acetonitrile 5.00 ml and cooled at 0° C. Triethylamine 0.16ml and methane sulfonyl chloride 0.10 ml 1.21 mmol were added theretoand the temperature was raised to room temperature. After 1 hour, themixture was partitioned by adding ether and brine. The organic layer waswashed with aqueous saturated sodium bicarbonate, dried over magnesiumsulfate anhydride and evaporated. A half about 0.55 mmol of the residueswas dissolved in N,N-dimethylformamide 5.00 ml, and 500 mg 3.34 mmol ofsodium iodide, 76.0 mg 0.55 mmol of potassium carbonate, and 202 mg 0.90mmol of 1-[2-(4-fluorophenoxy)ethyl]piperazine were added thereto, andthe mixture was heated at 60° C. Brine was added to the reaction mixturewhich was then extracted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate anhydride, andevaporated. The residue was purified by Chromatorex NH silica gel columnchromatography (ethyl acetate/hexane system), whereby the titlecompound, 215 mg 0.47 mmol, 86.0%, was obtained as a yellow syrup.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.92 (d, J=6.78 Hz, 3H), 1.21 (d,J=6.59 Hz, 3H), 1.18-1.32 (m, 1H), 1.58-1.71 (m, 1H), 1.72-1.82 (m, 1H),2.01-2.12 (m, 1H), 2.17-2.27 (m, 1H), 2.28-2.68 (m, 10H), 2.79 (t,J=5.86 Hz, 2H), 4.05 (t, J=5.86 Hz, 2H), 6.80-6.87 (m, 2H), 6.92-6.99(m, 2H), 7.15 (d, J=3.80 Hz, 1H), 7.51 (d, J=3.80 Hz, 1H).

ESI-MS; 455 (MH+).

Example 115 Synthesis of1-[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

The title compound was obtained by using1-[2-(3-fluorophenoxy)ethyl]piperazine in the same manner as in theabove example.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.92 (d, J=6.78 Hz, 3H), 1.21 (d,J=6.78 Hz, 3H), 1.18-1.32 (m, 1H), 1.58-1.71 (m, 1H), 1.72-1.82 (m, 1H),2.06 (sept, J=6.78 Hz, 1H), 2.17-2.27 (m, 1H), 2.28-2.68 (m, 10H), 2.80(t, J=5.86 Hz, 2H), 4.07 (t, J=5.86 Hz, 2H), 6.68-6.71 (m, 3H), 7.15 (d,J=4.00 Hz, 1H), 7.17-7.24 (m, 1H), 7.51 (d, J=4.00 Hz, 1H).

ESI-MS; 455 (MH+).

Example 116 Synthesis of1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine

The title compound (yield, 86.9%; 336 mg) was obtained from1-[2-(3-fluorophenoxy)ethyl]piperazine 323 mg and4-cyano-5-methyl-4-(2-thienyl)hexanol 200 mg in the same manner as inExample 114.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.90 (d, J=6.59 Hz, 3H), 1.18 (d,J=6.59 Hz, 3H), 1.25-1.38 (m, 1H), 1.58-1.70 (m, 1H), 1.72-1.82 (m, 1H),2.06 (sept, J=6.59 Hz, 1H), 2.11-2.21 (m, 1H), 2.27-2 2.64 (m, 10H),2.79 (t, J=5.86 Hz, 2H), 4.07 (t, J=5.86 Hz, 2H), 6.58-6.70 (m, 3H),6.94 (dd, J=3.60 Hz, 5.20 Hz, 1H), 7.11 (dd; J=1.2 Hz, 3.6 Hz, 1H),7.16-7.24(m, 1H), 7.25 (dd, J=1.20 Hz, 5.20 Hz).

ESI-MS; 430 (MH+).

Example 117 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine

In a nitrogen atmosphere,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine100 mg, thiophene-3-boric acid 53 mg, and a tetrakistriphenyl phosphinepalladium complex 24 mg were dissolved in toluene 4.0 ml, and 10%aqueous sodium bicarbonate was added thereto, and the atmosphere wasreplaced by nitrogen, and the mixture was heated for 4 hours underreflux with heating. The reaction mixture was cooled and thenpartitioned by adding water and ethyl acetate. The organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride and evaporated. The residue was purified by NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound (21 mg, 21%) was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.63 (m, 1H), 1.83-1.95 (m, 1H),2.05-2.20 (m, 2H), 2.23-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.45-2.60 (m,4H), 2.81 (t, J=6.0 Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 6.80-6.84 (m, 1H),7.12-7.14 (m, 1H), 7.16-7.20 (m, 1H), 7.25-7.32 (m, 2H), 7.33-7.38 (m,2H), 7.42-7.45 (m, 6H), 7.42-7.45 (m, 1).

This free compound 21 mg was treated in a usual manner to give thehydrochloride 17 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 0.67 (d, J=6.4 Hz, 3H), 1.11 (d,J=6.8 Hz, 3H), 1.20-1.30 (m, 1H), 1.55-1.70 (m, 1H), 2.05-2.30 (m, 3H),3.20-3.80 (m, 12H), 4.42 (brs, 2H), 6.90-6.95 (m, 1H), 7.30-7.40 (m,4H), 7.40-7.50 (m, 4H), 7.55-7.58 (m, 1H), 7.62-7.66 (m, 1H), 7.88-7.92(m, 1H).

ESI-Mass; 488 (MH+).

Example 118 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenoxyl]ethyl}piperazine

In a nitrogen atmosphere,1-[(4-cyano-5-methyl-4-phenyl)hexyl)-4-(2-(2-bromophenoxy)ethyl]piperazine100 mg, 6-vinyl-2-methylpyridine 49 mg, palladium acetate 4.6 mg andtris(2-methylphenyl) phosphine 12.5 mg were dissolved inN,N-dimethylformamide 4.0 ml, and triethylamine 1 ml was added thereto,and the mixture was stirred for 10 hours under reflex with heating. Thereaction mixture was cooled, filtered through Celite, and partitioned byadding water and diethyl ether. The organic layer was washed with waterand then with brine, dried over magnesium sulfate anhydride andevaporated. The residues were purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(115 mg, 100%) was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.83-1.93 (m, 1H),2.05-2.20 (m, 2H), 2.20-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.50-2.70 (m,4H), 2.56 (s, 3H), 2.89 (t, J=5.9 Hz, 2H), 4.16 (t, J=5.9 Hz, 2H), 6.88(d, J=8.4 Hz, 1H), 6.94-7.00 (m, 2H), 7.18-7.38 (m, 6H), 7.52 (t, J=7.7Hz, 1H), 7.62-7.66 (m, 1H), 7.87 (d, J=16.7 Hz, 1H).

This free compound 115 mg was treated in a usual manner to give thehydrochloride 110 mg of the title compound.

Hydrochloride;

ESI-Mass; 523 (MH+).

Example 119 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine

In a nitrogen atmosphere,1-[(4-cyano-5-methyl-4-phenyl)hexyl)-4-[2-(3-bromophenoxy)ethyl]piperazine100 mg, zinc cyanide 24 mg, and a tetrakistriphenyl phosphine palladiumcomplex 24 mg were dissolved in N,N-dimethylformamide 4.0 ml and heatedand stirred for 9 hours under reflex. The reaction mixture was cooled,filtered through Celite, and partitioned by adding water and diethylether. The organic layer was washed with water and then with brine,dried over magnesium sulfate anhydride and evaporated. The residue waspurified by NH silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (63 mg, 71%) was obtained as acolorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.83-1.95 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.48 (m, 4H), 2.48-2.65 (m,4H), 2.80 (t, J=5.7 Hz, 2H). 4.09 (t, J=5.7 Hz, 2H), 7.10-7.17 (m, 2H),7.21-7.39 (m, 7H).

This free compound 63 mg was treated in a usual manner to give thehydrochloride 58 mg of the title compound.

Hydrochloride;

ESI-Mass; 431 (MH+).

Example 120 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenylphenoxy)ethyl]piperazine120-1) 2-(3-Phenylphenoxy)ethanol

In a nitrogen atmosphere, 3-phenylphenol 2.65 g, 2-bromoethanol 2.92 gand potassium carbonate 6.51 g were dissolved in N,N-dimethylformamide16 ml and stirred at 100° C. After 5 hours, the reaction mixture wascooled to room temperature and partitioned by adding water and diethylether. The organic layer was washed with water and then with brine,dried over magnesium sulfate anhydride, and evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetatesystem), whereby the title compound (1.78 g, 53%) was obtained as acolorless crystalline.

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 2.18-2.24 (m, 1H), 3.96-4.00 (m, 2H),4.14 (t, J=4.8 Hz, 2H), 6.88-6.92 (m, 1H), 7.13-7.16 (m, 1H), 7.18-7.22(m, 1H), 7.32-38 (m, 2H), 7.40-7.45 (m, 2H), 7.55-7.59 (m, 2H).

120-2)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[-2-(3-phenylphenoxy)ethyl]piperazine

In a nitrogen atmosphere, 2-(3-phenylphenoxy)ethanol 68 mg andtriethylamine 0.13 ml were dissolved in acetonitrile 6 ml in an icebath, and methane sulfonyl chloride 40 mg was added thereto. After themixture was stirred for 3 hours, sodium iodide 142 mg and a solution of1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine 90 mg in acetonitrile 3ml were added thereto, and the mixture was stirred for 15 hours underreflux with heating. After cooling, the reaction mixture was partitionedby adding water and ethyl acetate. The organic layer was washed withwater and then with brine, dried over magnesium sulfate anhydride andevaporated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate system), whereby the title compound(127 mg, 84%) was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.8 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.45-2.65 (m,4H), 2.81 (t, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 2H), 6.85-6.90 (m, 1H),7.11-7.14 (m, 1H), 7.15-7.19 (m, 1H), 7.25-7.45 (m, 9H), 7.55-7.60 (m,2H).

This free compound 127 mg was treated in a usual manner to give thehydrochloride 115 mg of the title compound.

Hydrochloride;

ESI-Mass; 482 (MH+).

Example 121 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine200 mg, acrylonitrile 0.08 ml, palladium acetate 9.3 mg, andtris(2-methylphenyl) phosphine 25 mg were dissolved inN,N-dimethylformamide 8.0 ml, and triethylamine 2.0 ml was addedthereto, and the mixture was heated in a sealed vessel at 100° C. for 12hours. The reaction mixture was cooled and then filtered through Celite,and partitioned by adding water and ethyl acetate. The organic layer waswashed with water and then with brine, dried over magnesium sulfateanhydride, and evaporated. The residue was purified by NH silica gelcolumn chromatography (hexane/ethyl acetate system), whereby the titlecompound (65 mg, 35%) was obtained as a colorless oil.

Free Compound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 0.77 (d, J=6.6 Hz, 3H), 1.05-1.20 (m,1H), 1.20 (d, J=6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.82-1.92 (m, 1H),2.05-2.20 (m, 2H), 2.25-2.30 (m, 2H), 2.30-2.45 (m, 4H), 2.45-2.65 (m,4H), 2.79 (t, J=5.9 Hz, 2H), 4.09 (t, J=5.9 Hz, 2H), 5.85 (d, J=16.8 Hz,1H), 6.64-7.40 (m, 10H).

This free compound 32 mg was treated in a usual manner to give thehydrochloride 30 mg of the title compound.

Hydrochloride;

ESI-Mass; 457 (MH+).

Example 122 Synthesis of1-[(4-Cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound 8.53 g, 85% was obtained as a colorless oil from4-cyano-5-methyl-4-phenylhexanoic acid 5.28 g and1-[2-(4-fluorophenoxy)ethyl]piperazine 5.38 g in the same manner as inExample 97-2).

Free Comound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm), 0.78 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.6Hz, 3H), 1.80-1.93 (m, 1H), 2.10-2.20 (m, 1H), 2.25-2.55 (m, 7H), 2.77(t, J=5.5 Hz, 2H), 3.20-3.40 (m, 2H), 3.45-3.70 (m, 2H), 4.03 (t, J=5.5Hz, 2H), 6.79-6.84 (m, 2H), 6.92-6.98 (m, 2H), 7.14-7.40 (m, 5H).

ESI-Mass; 438 (MH+).

Example 123 Synthesis of1-[(4-Cyano-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine

The title compound 874 mg, 67% was obtained as a pale yellow oil from(4-cyano-4-phenyl)butylaldehyde 720 mg and1-[2-(4-fluorophenoxy)ethyl]piperazine 689 mg in the same manner as inExample 1.

Free Comound;

¹H-NMR (400 MHz, CDCl₃); δ (ppm) 1.60-1.70 (m, 2H), 1.86-2.00 (m, 2H),2.37 (t, J=7.2 Hz, 2H), 2.40-2.54 (m, 4H), 2.54-2.66 (m, 4H), 2.76-2.82(m, 2H), 3.84-3.88 (m, 1H), 4.02-4.08 (m, 2H), 6.81-6.86 (m, 2H),6.93-6.98 (m, 2H), 7.30-7.40 (m, 5H).

This free product 874 mg was treated in a usual manner to give thehydrochloride 890 mg of the title compound.

Hydrochloride;

¹H-NMR (400 MHz, DMSO-d₆); δ (ppm) 1.75-1.85 (m, 2H), 1.85-2.02 (m, 2H),3.12-3.22 (m, 2H), 3.22-3.82 (m, 10H), 4.28-4.38 (m, 3H), 7.01-7.06 (m,2H), 7.13-7.20 (m, 2H), 7.34-7.38 (m, 1H), 7.40-7.46 (m, 4H).

ESI-Mass; 382 (MH+).

What is claimed is:
 1. An N,N-substituted cyclic amine compoundrepresented by the following formula (VIII):

wherein A represents an aryl group which may be substituted, aheteroaryl group which may be substituted, an aralkyl group which may besubstituted, or a heteroaryl alkyl group which may be substituted; Erepresents a group represented by the formula —CO— or a grouprepresented by the formula —CHOH—; G represents an oxygen atom, a sulfuratom, and a group represented by the formula —NR¹⁰—, wherein R¹⁰represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl, alower acyl group or a lower alkyl sulfonyl group, a group represented by—CO—, a group represented by —COO—, a group represented by the formula—CONR¹¹, wherein R¹¹ represents a hydrogen atom or a lower alkyl group,a group represented by the formula —NR¹²CO—, _wherein R¹² represents ahydrogen atom or a lower alkyl group, a group represented by the formula—SO—, a group represented by the formula —SO₂—, a group represented bythe formula —SONR¹³—, wherein R¹³ represents a hydrogen atom or a loweralkyl group, a group represented by the formula —NR¹⁴SO—, wherein R¹⁴represents a hydrogen atom or a lower alkyl group, a group representedby the formula —SO₂NR¹⁵— wherein R¹⁵ represents a hydrogen atom or alower alkyl group, a group represented by the formula —NR¹⁶SO₂—, whereinR¹⁶ represents a hydrogen atom or a lower alkyl group, a grouprepresented by the formula >C═N—OR¹⁷, wherein R¹⁷ represents a hydrogenatom or a lower alkyl group, a group represented by the formula—NHCONH—, a group represented by the formula —NHCSNH—, a grouprepresented by the formula —C(═NH)NH, a group represented by the formula—NHC(═NH)—, a group represented by the formula —OCOS—, a grouprepresented by the formula —SCOO—, a group represented by the formula—OCOO—, a group represented by the formula —NHCOO—, a group representedby the formula —OCONH—, a group represented by the formula—CO(CH₂)_(s)O—, a group represented by the formula —CHOH— or a grouprepresented by the formula —CHOH(CH₂)_(s)O—, wherein s represents 0 oran integer of 1 to 6; J represents an aryl group which may besubstituted or a heteroaryl group which may be substituted; R¹represents a hydrogen atom, a halogen atom, a hydroxy group, a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a lowercycloalkyl group, a hydroxy lower alkyl group, a lower alkoxyalkylgroup, a cyano-lower alkyl group, a halogenated lower alkyl group, anoptionally N-substituted amino-lower alkyl group, a group represented bythe formula —NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ may be the same as ordifferent from each other and each represents a hydrogen atom or a loweralkyl group, an aralkyl group, a morpholinyl group, a thiomorpholinylgroup, a piperidyl group, a pyrrolidinyl group or a piperazinyl group;Alk represents a linear or branched lower alkylene group; and n, v, x, wand y are independent of each other and each represents 0 or 1, and prepresents 2 or 3, provided that x is 1 when G is —CO—, or apharmacologically acceptable salt thereof.
 2. A N,N-substituted cyclicamine compound represented by the following formula (I):

wherein A represents an aryl group which may be substituted, aheteroaryl group which may be substituted, an aralkyl group which may besubstituted or a heteroaryl alkyl group which may be substituted; Erepresents a group represented by the formula —CO— or a grouprepresented by the formula —CHOH—; G represents an oxygen atom, a sulfuratom, and a group represented by the formula —NR¹⁰—, wherein R¹⁰represents a hydrogen atom, a lower alkyl group, a lower acyl group or alower alkyl sulfonyl group, a group represented by —OC—, a grouprepresented by —COO—, a group represented by the formula —CONR¹¹,wherein R¹¹ represents a hydrogen atom or a lower alkyl group, a grouprepresented by the formula —NR¹²CO—, wherein R¹² represents a hydrogenatom or a lower alkyl group, a group represented by the formula —SO—, agroup represented by the formula —SO₂—, a group represented by theformula —SONR¹³ —, wherein R¹³ represents a hydrogen atom or a loweralkyl group, a group represented by the formula —NR¹⁴SO—, wherein R¹⁴represents a hydrogen atom or a lower alkyl group, a group representedby the formula —SO₂NR¹⁵—, wherein R¹⁵ represents a hydrogen atom or alower alkyl group, a group represented by the formula —NR¹⁶SO₂—, whereinR¹⁶ represents a hydrogen atom or a lower alkyl group, a grouprepresented by the formula >C═N—OR¹⁷, wherein R¹⁷ represents a hydrogenatom or a lower alkyl group, a group represented by the formula—NHCONH—, a group represented by the formula —NHCSNH—, a grouprepresented by the formula —C(═NH)NH—, a group represented by theformula —NHC(═NH)—, a group represented by the formula —OCOS—, a grouprepresented by the formula —SCOO—, a group represented by the formula—OCOO—, a group represented by the formula —NHCOO—, a group representedby the formula —OCONH—, a group represented by the formula—CO(CH₂)_(s)O—, a group represented by the formula —CHOH— or a grouprepresented by the formula —CHOH(CH₂)_(s)O—, wherein s is 0 or aninteger of 1 to 6; J represents an aryl group which may be substitutedor a heteroaryl group which may be substituted; R¹ represents a loweralkyl group, a cycloalkyl group, a group represented by the formula—NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ may be the same as or different from eachother and each represents a hydrogen atom or a lower alkyl group, amorpholinyl group, a thiomorpholinyl group, a piperidyl group, apyrrolidnyl group or a piperazinyl group; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ andR⁹ may be the same as or different from each other and each represents ahydrogen atom or a lower alkyl group; and m, o, q and r may be the sameas or different from each other and each represents 0 or an integer of 1to 6, n is 0 or 1, and p is 2 or 3, provided that q is an integer of 1when G is —CO—, or a pharmacologically acceptable salt thereof.
 3. Thecompound of claim 2 represented by the following formula (II):

wherein A, E, G, J, R¹, m, n, o, p, q and r have the same meanings asdefined above, or a pharmacologically acceptable salt thereof.
 4. Thecompound of claim 2 represented by the following formula (III):

wherein A, G, J, R¹, m, p and q have the same meanings as defined above,or a pharmacologically acceptable salt thereof.
 5. A N,N-substitutedcyclic amine compound represented by the following formula (IV):

wherein R¹ represents a hydrogen atom, a halogen atom, a hydroxy group,a lower alkyl group, a lower alkenyl group, a lower alkynyl group, alower cycloalkyl group, a hydroxy lower alkyl group, a lower alkoxyalkylgroup, a cyano-lower alkyl group, a halogenated lower alkyl group, anoptionally N-substituted amino-lower alkyl group, a group represented bythe formula —NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ may be the same as ordifferent from each other and each represents a hydrogen atom or a loweralkyl group, an aralkyl group, a morpholinyl group, a thiomorpholinylgroup, a piperidyl group, a pyrrolidinyl group or a piperazinyl group; mand q may be the same as or different from each other and eachrepresents 0 or an integer of 1 to 6; p is 2 or 3; R²⁰ and R²¹ are thesame as or different from each other and each represents a hydrogenatom, a halogen atom, a hydroxy group, a mercapto group, a lower alkylgroup, a lower alkoxy group, a hydroxymethyl group, a nitro group, anamino group which may be substituted, a cyano group, a carboxyl group, alower alkoxy carbonyl group, a lower thioalkoxy group, a lower alkylsulfonyl group, a lower acyl group, a halogenated lower alkyl group, anaryl group which may be substituted, a heteroaryl group which may besubstituted, an aryloxy group, an aralkyloxy group, a loweralkoxycarbonylalkoxy group or a hydroxy lower alkoxy group, and R²⁰groups or R²¹ groups may form an alicyclic group which may besubstituted, or a heterocylclic group or alkylene dioxy group which maybe substituted; and j and t may be the same as or different from eachother and each represents 0 or an integer of 0 or 1 to 5, or apharmacologically acceptable salt thereof.
 6. The compound of claim 1,2, 3, 4, or 5, wherein said compound is selected from the groupconsisting of: (1)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(2)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)propyl]piperazine,(3)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine,(4)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine,(5)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-fluorophenoxy)propyl]piperazine,(6) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine,(7) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-phenoxyethyl)piperazine,(8)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine,(9)1-[4-cyano-5-methyl-4-(4-methylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(10)1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(11)1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(12)1-[4-cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(13)1-[4-cyano-5-methyl-4-(4-hydroxymethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(14)1-[4-cyano-5-methyl-4-(4-hydroxyiminomethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(15)1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(16)1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(17)1-[4-cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(18)1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(19)1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(20)1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(21)1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(22)1-{[4-cyano-5-methyl-4-(2-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(23)1-{[4-cyano-5-methyl-4-(3-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(24)1-{[4-cyano-5-methyl-4-(4-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(25)1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(26)1-[(4-cyano-4-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(27)1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(28) 1-[(4-cyano-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(29) 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(30)1-[(4-cyano-6-methyl-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(31)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-fluorophenoxy)ethyl]piperazine,(32)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine,(33)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)pentyl]piperazine,(34)1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-fluorophenoxy)ethyl]piperazine,(35)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-difluorophenoxy)ethyl]piperazine,(36)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine,(37)1-{[4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(38)1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(39)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine,(40)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine,(41)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine,(42)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine,(43)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminophenoxy)ethyl]piperazine,(44)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-acetamidophenoxy)ethyl]piperazine,(45)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophenoxy)ethyl]piperazine,(46)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanophenoxy)ethyl]piperazine,(47)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperazine,(48)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine,(49)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylthio)ethyl]piperazine,(50)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylsulfonyl)ethyl]piperazine,(51)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]piperazine,(52)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylamino]ethyl}piperazine,(53)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-acetylamino]ethyl}piperazine,(54)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methanesulfonylamino]ethyl}piperazine,(55)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine,(56)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine,(57)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine,(58)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-Isopropylamino)ethyl]piperazine,(59)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine,(60)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-fluorophenyl)propyl]piperazine,(61)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)acetyl]piperazine,(62)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine,(63)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine,(64)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoylamino)ethyl]piperazine,(65)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine,(66)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine,(67)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)sulfamoyl]ethyl}piperazine,(68)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylsulfamoyl]ethyl}piperazine,(69)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-fluorobenzenesulfonylamino)ethyl]piperazine,(70)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-fluorophenylthio)carbonyloxy]ethyl}piperazine,(71)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine,(72)1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl-4-[2-(4-fluorophenoxy)ethyl]piperazine,(73)1-(2-hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenoxy)ethyl]piperazine,(74)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzylphenoxy)ethyl]piperazine,(75)1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(76)1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(77)1-[4-cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(78)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-fluorophenoxy)ethyl]piperazine,(79)1-[(4-cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(80)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-fluorophenoxy)ethyl]piperazine,(81)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-fluorophenoxy)ethyl]piperazine,(82)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-fluorophenoxy)ethyl]piperazine,(83)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-Isopropylanilino)ethyl]piperazine,(84)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylanilino)ethyl]piperazine,(85)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(4-Isopropylanilino)ethyl]}piperazine,(86)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(3-Isopropylanilino)ethyl]}piperazine,(87)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(2-Isopropylanilino)ethyl]}piperazine,(88)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine,(89) Synthesis of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-quinolyloxy)ethyl]piperazine,(90)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-isoquinolyloxy)ethyl]piperazine,(91)1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(92)1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,(93)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine,(94)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine,(95)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-quinolyloxy)ethyl]piperazine,(96)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine,(97)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine,(98)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-fluorophenoxy)ethyl]piperazine,(99)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-quinazolinyloxy)ethyl]piperazine,(100)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine,(101)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine,(102)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine,(103)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine,(104)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine,(105)1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine,(106)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinyloxy)ethyl]piperazine,(107)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine,(108)1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,(109)1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine,(110)1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine,(111)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine,(112)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenoxy]ethyl}piperazine,(113)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine,(114)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenylphenoxy)ethyl]piperazine,(115)1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine,(116)1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,and (117)1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine, or apharmacologically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising: the N,N-substituted cyclic amine compound asclaimed in any of claims 1, 2 or 5 or a pharmacologically acceptablesalt thereof; and a pharmaceutically acceptable carrier.
 8. A method oftreating and improving the diseases against which inhibitory action onP/Q type calcium channel is effective, comprising administering aneffective amount of the N,N-substituted cyclic amine compound as claimedin any of claims 1, 2 or 5 or a pharmacologically acceptable saltthereof as the active ingredient to a patient in need thereof.
 9. Amethod of treating and improving the diseases against which aninhibitory action on N type calcium channel is effective, comprisingadministering an effective amount of the N,N-substituted cyclic aminecompound as claimed in any of claims 1, 2 or 5 or a pharmacologicallyacceptable salt thereof to a patient in need thereof.
 10. A method forinhibiting the death of nerve cells or for protecting brain nerve cells,comprising administering an effective amount of the N,N-substitutedcyclic amine compound as claimed in any of claims 1, 2 or 5 or apharmacologically acceptable salt thereof to a patient in need thereof.11. A method of treating or improving a nerve disease, comprisingadministering an effective amount of the N,N-substituted cyclic aminecompound as claimed in any of claims 1, 2 or 5 or a pharmacologicallyacceptable salt thereof to a patient in need thereof.
 12. The method asclaimed in claim 11, wherein the nerve cell disease is one diseaseselected from the group consisting of acute ischemic stroke, cerebralapoplexy, cerebral infarction, head trauma, cerebral nerve cell death,Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis,Huntington disease, cerebral circulatory metabolism disturbance,cerebral function disturbance, pain, spasm, schizophrenia, migraine,epilepsy, maniac-depressive psychosis, nerve degenerative diseases,cerebral ischemia, AIDS dementia complications, edema, anxiety disorder(generalized anxiety disorder) and diabetic neuropathy.
 13. Apharmaceutical composition comprising a pharmacologically effectiveamount of the N,N-substituted cyclic amine compound as claimed in any ofclaims 1, 2 or 5 or a pharmacologically acceptable salt thereof; apharmacologically acceptable carrier; and at least one ingredientselected from the group consisting of a filler, a binder, adisintegrator, a lubricant, a coloring agent, and a taste and odorcorrectives.
 14. A method of treating a disease against which calciumantagonism is effective, which comprises administering apharmacologically effective amount of N,N-substituted cyclic aminecompound as claimed in any of claims 1, 2 or 5 or a pharmacologicallyacceptable salt thereof to a patient in need thereof.
 15. The compoundaccording to claim 1, wherein said compound is one compound selectedfrom the group consisting of1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorphenoxy)ethyl]piperazine,1-[4-cyano-5-methyl-4-(4-methylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-{[4-cyano-5-methyl-4-(2-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-{[4-cyano-5-methyl-4-(3-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-{[4-cyano-5-methyl-4-(4-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylamino]ethyl}piperazine,1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[(4-cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(3-Isopropylanilino)ethyl]}piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine,1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-quinolyloxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine,1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine,1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine.16. The method of claim 8, wherein said pharmaceutical composition isadministered at a dosage of 0.01 to 1000 mg per day.